wwwachab_dev.pl

#!/usr/bin/perl

##### wwwachab.pl ####

# Author : Thomas Guignard 2023

# Description :
# Create an User friendly Excel file from an MPA annotated VCF file.


use strict;
use warnings;
use Getopt::Long;
use Excel::Writer::XLSX;
use Switch;
use File::Basename;
#use Pod::Usage;
#use List::Util qw(first);
#use Data::Dumper;

#parameters
my $man = "USAGE : \nperl wwwachab.pl
\n--vcf <vcf_file> (mandatory)
\n--outDir <output directory (default = current dir)>
\n--outPrefix <output file prelifx (default = \"\")>
\n--candidates <file with end-of-line separated gene symbols of interest (it will create more tabs, if '#myPathology' is present in the file, a 'myPathology' tab will be created) >
\n--phenolyzerFile <phenolyzer output file suffixed by predicted_gene_scores (it will contribute to the final ranking and top50 genes will be added in METADATA tab) >
\n--popFreqThr <allelic frequency threshold from 0 to 1 default=0.01 (based on gnomAD_genome_ALL or on the first field of --gnomadGenome argument) >
\n--trio (requires case dad and mum option to be filled, but if case dad and mum option are filled, trio mode is automatically activated)
\n\t--case <index_sample_name> (required with trio option)
\n\t--dad <father_sample_name> (required with trio option)
\n\t--mum <mother_sample_name> (required with trio option)
\n--customInfoList  <comma separated list of vcf annotation INFO names (each of them will be added in a new column)>
\n--filterList <comma separated list of VCF FILTER to output (default='PASS', included )>
\n--cnvGeneList <File with gene symbol + annotation (1 tab separated), involved by parallel CNV calling >
\n--customVCF <VCF format File with custom annotation (if variant matches then INFO field annotations will be added in new column)>
\n--mozaicRate <mozaic rate value from 0 to 1, it will color 0/1 genotype according to this value  (default=0.2 as 20%)>
\n--mozaicDP <ALT variant Depth, number of read supporting ALT, it will give darker color to the 0/1 genotype  (default=5)>
\n--newHope (only popFreqThr filter is applied (no more FILTER nor MPA_ranking))>
\n--affected <comma separated list of samples affected by phenotype (assuming they support the same genotype >
\n--favouriteGeneRef <File with transcript references to extract in a new column (1 transcript by line) >
\n--filterCustomVCF <integer value, penalizes variant if its frequency in the customVCF is greater than [value] (default key of info field : found=[value])  >
\n--filterCustomVCFRegex <string pattern used as regex to search for a specific field to filter customVCF (default key of info field : 'found=')  >
\n--addCustomVCFRegex (customVCF field matched with customVCFRegex will be added in a new column - it requires customVCF option -  default regex is 'found=') 
\n--pooledSamples <comma separated list of samples that are pooled (e.g. parents pool in trio context)  >
\n--IDSNP <comma separated list of rs ID for identity monitoring (it will convert 0/0 genotype into 0/1 if at least 1 read support ALT base and it will flag cell in yellow, e.g. rs4889990,rs2075559)  >
\n--sampleSubset <comma separated list of samples only processed by Achab to the output >
\n--addCaseDepth (case Depth will be added in a new column)
\n--addCaseAB (case Allelic Balance will be added in a new column)
\n--intersectVCF <VCF format File for comparison (if variant matches then 'yes' will be added in new 'intersectVCF' column) >
\n--poorCoverageFile <poor Coverage File (it will annotate OMIM genes if present in the 4th column -requires OMIM genemap2 File- and create an excel file )>
\n--genemap2File <OMIM genemap2 file (it will help to annotate OMIM genes in poor coverage file ) >
\n--skipCaseWT (only if trio mode is activated or in 'duo' if case+dad are defined or if case+mum are defined , it will skip variant if case genotype is 0/0 ) 
\n--hideACMG (ACMG tab will be empty but information will be reported in the gene comment) 
\n--gnomadGenome <comma separated list of gnomad genome annotation fields that will be displayed as gnomAD_Genome comments. First field of the list will be filtered regarding to popFreqThr argument. (default fields are hard-coded gnomAD_genome_ALL like)  > 
\n--gnomadExome <comma separated list of gnomad exome annotation fields that will be displayed as gnomAD comments. (default fields are hard-coded gnomAD_exome_ALL like) > 
\n--MDAPIkey <Path to File containing only MobiDetails API key (default file is MD.apikey in the achab folder) >
\n\n-v|--version < return version number and exit > ";

my $versionOut = "achab version www:1.0.13";

#################################### VARIABLES INIT ########################

#catch argument for METADATA
my $achabArg = "";
foreach my $a(@ARGV){
    $achabArg .= $a."   ";
}



my $help;
my $version;
my $current_line;
my $incfile = "";
my $outDir = ".";
my $outPrefix = "";
my $case = "";
my $mum = "";
my $dad = "";
my $caller = "";
my $trio;
my $popFreqThr = "";
my $filterList = "";
my @filterArray;
my $newHope;
my $sampleNames = "";
my @sampleList;
my $customInfoList = "";
my @custInfList;
my $mozaicRate = "" ;
my $mozaicDP = "";


#stuff for files
my $candidates = "";
my %candidateGene;
my $candidates_line;

my $phenolyzerFile = "";
my $phenolyzer_Line;
my @phenolyzer_List;
my %phenolyzerGene;

my $cnvGeneList = "";
my %cnvGene;
my $cnvGene_Line;
my @cnvGene_List;

my $customVCF_File = "";
my $customVCF_Line;
my @customVCF_List;
my %customVCF_variant;
#threshold to filter out bias related frequent variants
my $filterCustomVCF = "";
my $filterCustomVCFRegex = "";
my $addCustomVCFRegex;

my $intersectVCF_File = "";
my $intersectVCF_Line;
my @intersectVCF_List;
my %intersectVCF_variant;

#vcf parsing and output
my @line;
my $variantID;
my @geneListTemp;
my @geneList;
my $mozaicSamples = "";
my $count = 0;

#Data structure
my @finalSortData;
my $familyGenotype;
my %hashFinalSortData;

my $worksheetTAG = "";

# favourite NM refGene
my $favouriteGeneRef = "";
my @geneRefArray;
my %geneRef_gene;
my $geneRef_line;

#affected samples
my $affected = "";    # next if affected_sample = case or dad or mum
my @affectedArray;
my %hashAffected;
my @nonAffectedArray;

#Variable for genotype checking
my @strangerNULL;
my @strangerREF;
my @strangerHTZ;
my @strangerHMZ;

#parents pool
my $pooledSamples = "";
my @pooledSamplesArray;
my %hashPooledSamples;


#identity monitoring
my $IDSNP = "";
my @IDSNPArray;
my %hashIDSNP;

#process only these samples
my $sampleSubset = "";
my @sampleSubsetArray;

#case options
my $addCaseDepth;
my $addCaseAB;
my $skipCaseWT;
my $duo;

#Poor coverage File and omim genemap2 file
my $genemap2_File = "";
my $genemap2_Line;
my @genemap2_List;
my %genemap2_variant;

my $poorCoverage_File = "";
my $poorCoverage_Line;
my @poorCoverage_List;
my %poorCoverage_variant;

#adapt gnomAD names
my $gnomadGenome_names = "";
my @gnomadGenome_List;
my $gnomadGenomeColumn = "gnomAD_genome_ALL";
my $gnomadExome_names = "";
my @gnomadExome_List;
my $gnomadExomeColumn = "gnomAD_exome_ALL";

my $hideACMG;

# METADATA

# inheritance checking test
my $dadVariant = 0;
my $mumVariant = 0;
my $caseDadVariant = 0;
my $caseMumVariant = 0;

my $vcfHeader = "";

my @buttonArray ;
my %tagsHash;

#URL corner
my $mdAPIkey = "";
my $md_line = "";
my $franklinURL = "https://franklin.genoox.com/clinical-db/variant/snp/";
my $build = "hg19";

#$arguments = GetOptions( "vcf=s" => \$incfile ) or pod2usage(-vcf => "$0: argument required\n") ;

GetOptions( 	"vcf=s"				=> \$incfile,
		"case=s"			=> \$case,
		"dad=s"				=> \$dad,
		"mum=s"				=> \$mum,
		"trio"				=> \$trio,
		"candidates:s"			=> \$candidates,
		"outDir=s"			=> \$outDir,
		"outPrefix:s"			=> \$outPrefix,
		"phenolyzerFile:s"		=> \$phenolyzerFile,
		"popFreqThr=s"			=> \$popFreqThr,
		"customInfoList:s"		=> \$customInfoList,
		"filterList:s"			=> \$filterList,
		"cnvGeneList:s"			=> \$cnvGeneList,
		"customVCF:s"			=> \$customVCF_File,
		"mozaicRate:s"			=> \$mozaicRate,
		"mozaicDP:s"			=> \$mozaicDP,
		"newHope"			=> \$newHope,
		"favouriteGeneRef:s"			=> \$favouriteGeneRef,
		"affected:s"		=> \$affected,
		"filterCustomVCF:s"			=> \$filterCustomVCF,
		"filterCustomVCFRegex:s"	=>	\$filterCustomVCFRegex,
		"addCustomVCFRegex"	=>	\$addCustomVCFRegex,
		"pooledSamples:s"	=>	\$pooledSamples,
		"IDSNP:s"	=>	\$IDSNP,
		"sampleSubset:s"		=> \$sampleSubset,
		"addCaseDepth"		=> \$addCaseDepth,
		"addCaseAB"		=> \$addCaseAB,
		"intersectVCF:s"	=> \$intersectVCF_File,
		"poorCoverageFile:s"	=> \$poorCoverage_File,
		"genemap2File:s"	=> \$genemap2_File,
		"skipCaseWT"		=> \$skipCaseWT,
		"hideACMG"		=> \$hideACMG,
		"gnomadGenome:s"	=> \$gnomadGenome_names,
		"gnomadExome:s"	=> \$gnomadExome_names,
		"MDAPIkey:s"	=> \$mdAPIkey,
		"help|h"			=> \$help,
		"version|v"   => \$version);




#check mandatory arguments
if(defined $version){
	print("$versionOut\n");
  exit(0);
}

if(defined $help){
	print("$man\n");
  exit(0);
}

if($incfile eq ""){
	die("$man\n");
}

#add underscore to output prefix
if($outPrefix ne ""){
	$outPrefix .= "_";
}

#define popFreqThr
if( $popFreqThr eq ""){
	$popFreqThr = 0.01;
}

#define filter List
if($filterList ne ""){
	@filterArray = split(/,/ , $filterList)
}
#default filter is PASS
unshift @filterArray, "PASS";


#check mozaic parameters
if($mozaicRate eq ""){
	$mozaicRate = 0.2;
}
if($mozaicDP eq ""){
	$mozaicDP = 5;
}


#check sample list param
if(defined $trio && ($case eq "" || $dad eq "" || $mum eq "")){
	die("TRIO option requires 3 sample names. Please, give --case, --dad and --mum sample name arguments.\n");
}

#define trio if case dad and mum are defined
if ($case ne "" && $dad ne "" && $mum ne ""){
	$trio = "";
}

#define duo (at least) if case and dad and not mum or case and mum and not dad are defined => concern skipCaseWT option only
if ($case ne "" ){
	if (($dad ne "" && $mum eq "") || ($dad eq "" && $mum ne "")){
 		$duo = "";
	}
}

#TODO affected samples
#define affected samples List
if($affected ne ""){
	chomp $affected;
	$affected =~ s/"//g; 
	if(defined $trio and $case ne ""){
		$affected =~ s/$case,//g; 
		$affected =~ s/,$dad//g; 
		$affected =~ s/$dad,//g; 
		$affected =~ s/,$mum//g; 
		$affected =~ s/$mum,//g; 
	}

	$affected =~ s/,,/,/g; 
	$affected =~ s/^,//g; 
	$affected =~ s/,$//g; 

	@affectedArray = split(/,/ , $affected);
	foreach my $affSample (@affectedArray){
		if (defined $hashAffected{$affSample}){
				#nothing to do
		}else{
			$hashAffected{$affSample} = "affected";
		}
	}
}


#pooled samples , check in header
if ($pooledSamples ne ""){
	chomp $pooledSamples;
	$pooledSamples =~ s/"//g ;
	$pooledSamples =~ s/^,//g; 
	$pooledSamples =~ s/,$//g; 
	@pooledSamplesArray = split(/,/ , $pooledSamples);
	foreach my $pooled (@pooledSamplesArray){
		if (defined $hashPooledSamples{$pooled}){
				#nothing to do
		}else{
			$hashPooledSamples{$pooled} = "pooled";
		}
	}
}



#ID monitoring
if ($IDSNP ne ""){
	chomp $IDSNP;
	@IDSNPArray = split(/,/ , $IDSNP);
	foreach my $rs (@IDSNPArray){
		if (defined $hashIDSNP{$rs}){
				#nothing to do
		}else{
			$hashIDSNP{$rs} = "ID";
		}
	}
}

#gnomad names
if ($gnomadGenome_names ne ""){
	chomp $gnomadGenome_names;
	@gnomadGenome_List = split(/,/ , $gnomadGenome_names);
	$gnomadGenomeColumn = $gnomadGenome_List[0]; 
}
if ($gnomadExome_names ne ""){
	chomp $gnomadExome_names;
	@gnomadExome_List = split(/,/ , $gnomadExome_names);
	$gnomadExomeColumn = $gnomadExome_List[0]; 
}



#Samples subset
if ($sampleSubset ne ""){
	chomp $sampleSubset;
	@sampleSubsetArray = split(/,/ , $sampleSubset);
}


print  STDERR "Starting a new fishing trip ... \n" ;
print  STDERR "Hope we will catch-a-lot ... \n" ;
print  STDERR "Processing vcf file ... \n" ;


open( VCF , "<$incfile" )or die("Cannot open vcf file $incfile") ;


#TODO check if header contains required INFO
#Parse VCF header to fill the dictionnary of parameters
print STDERR "Parsing VCF header in order to get sample names and to check if required informations are present ... \n";
my %dicoParam;

my $refGene = 'refGene';
while( <VCF> ){
	$current_line = $_;

	chomp $current_line;

    #filling dicoParam with VCF header INFO and FORMAT

    if ($current_line=~/^##/){

        $vcfHeader .= $_;
	
	#deduce genome build from header , like bcftools command line including with genome fasta 
	if ($current_line=~/38\.fa/){
		$build = "hg38";
	}

		

	  unless ($current_line=~/Description=/){ next }
      #DEBUG print STDERR "Header line\n";

      if ($current_line =~ /ID=(.+?),.*?Description="(.+?)"/){


		$dicoParam{$1}= $2;
		if ($1 eq "Func.refGeneWithVer") {$refGene = "refGeneWithVer"}
		#DEBUG      print STDERR "info : ". $1 . "\tdescription: ". $2."\n";


		next;

      }else {print STDERR "pattern not found in this line: ".$current_line ."\n";next}

	}elsif($current_line=~/^#CHROM/){
		#check sample names or die

        $vcfHeader .= $_;


		if (defined $trio){
			#check if case sample name is found
			unless ($current_line=~/\Q$case/){die("$case is not found as a sample in the VCF, please check case name.\n$current_line\n")}
			unless ($current_line=~/\Q$dad/){die("$dad is not found as a sample in the VCF, please check dad name.\n$current_line\n")}
			unless ($current_line=~/\Q$mum/){die("$mum is not found as a sample in the VCF, please check mum name.\n$current_line\n")}
		}

		@line = split (/\t/ , $current_line);


		for( my $sampleIndex = 9 ; $sampleIndex < scalar @line; $sampleIndex++){


			if ($sampleSubset ne ""){
				switch ($line[$sampleIndex]){
					case (\@sampleSubsetArray) {
						print STDERR "Found Sample ".$line[$sampleIndex]."\n";
						push @sampleList, $line[$sampleIndex];
					}else {
						print STDERR "Found Sample ".$line[$sampleIndex]."\t--ignored\n";
						next;
					}
				}
			}else{

				print STDERR "Found Sample ".$line[$sampleIndex]."\n";
				push @sampleList, $line[$sampleIndex];
			}
			
			

			#populate non affected-samples array
			if (defined $hashAffected{$line[$sampleIndex]} or (defined $trio and ($line[$sampleIndex] eq $case or $line[$sampleIndex] eq $dad or $line[$sampleIndex] eq $mum))  ){
				#do nothing

			}else{
				push @nonAffectedArray, $line[$sampleIndex];
			}

			#for each final position for sample
#			foreach my $finCol (keys %dicoSamples){
    	    #DEBUG
#				if ($dicoSamples{$finCol}{'columnName'} eq "Genotype-".$line[$sampleIndex] ){
#					$dicoSamples{$finCol}{'columnIndex'} =  $sampleIndex;
#					last;
#				}
#			}
#			foreach my $name (@sampleList)
				#if($line[$sampleIndex]

		}

		#TODO check if all samples in affected list or in PooledSamples list are present or die


		#specify which sample will be the first in the output, to get genotype comment
		# TODO check if it's Ok
		if (! defined $trio){
				if (@affectedArray){
					$case = $affectedArray[0];
				}elsif($case eq ""){
					$case = $sampleList[0];
				}
		}

		#exclude to treat trio with too much sample
		print STDERR "\nTotal Samples : ".scalar @sampleList."\n";

		if(scalar @sampleList > 3 && defined $trio && scalar @affectedArray == 0 ){
			# TODO check if all affected samples and case , dad and mum are present
			#die("Found more than 3 samples. TRIO analysis is not supported with more than 3 samples.\n");
		}



	}else {last}

}
close(VCF);



# Create a new Excel workbook
#
my $workbook;

if ($outDir eq "." || -d $outDir) {
	if(defined $newHope){
		# Create a "new hope Excel" aka NON-PASS + MPA_RANKING=8 variants
		$workbook = Excel::Writer::XLSX->new( $outDir."/".$outPrefix."achab_catch_newHope.xlsx" );
	}else{
		$workbook = Excel::Writer::XLSX->new( $outDir."/".$outPrefix."achab_catch.xlsx" );
	}
}else {
 	die("No directory $outDir");
}


#create default color background when pLI values are absent
my $format_pLI = $workbook->add_format(bg_color => '#FFFFFF');
my $format_mozaic = $workbook->add_format(bg_color => 'purple');
#$format_pLI -> set_pattern();

#create LOEUF decile associated colors dico

my %dicoLOEUFformatColor;

$dicoLOEUFformatColor{'0.0'} = '#FF0000';
$dicoLOEUFformatColor{'1.0'} = '#FF3300';
$dicoLOEUFformatColor{'2.0'} = '#FF6600';
$dicoLOEUFformatColor{'3.0'} = '#FF9900';
$dicoLOEUFformatColor{'4.0'} = '#FFCC00';
$dicoLOEUFformatColor{'5.0'} = '#FFFF00';
$dicoLOEUFformatColor{'6.0'} = '#BFFF00';
$dicoLOEUFformatColor{'7.0'} = '#7FFF00';
$dicoLOEUFformatColor{'8.0'} = '#3FFF00';
$dicoLOEUFformatColor{'9.0'} = '#00FF00';
$dicoLOEUFformatColor{'.'} = '#FFFFFF';




# Add all worksheets

#$tagsHash{'ALL'} = 'ALL_'.$popFreqThr ;

my $worksheet = $workbook->add_worksheet('ALL_'.$popFreqThr);
$worksheet->freeze_panes( 1, 0 );    # Freeze the first row
my $worksheetLine = 1;

$tagsHash{'ACMG'}{'label'} = "DS_ACMG" ;
$tagsHash{'ACMG'}{'count'} = 0 ;
my $worksheetACMG = $workbook->add_worksheet('DS_ACMG');
$worksheetACMG->freeze_panes( 1, 0 );    # Freeze the first row
my $worksheetLineACMG = 1;

# Meta Data worksheet
$tagsHash{'META'}{'label'}  = "METADATA" ;
$tagsHash{'META'}{'count'}  = 1 ;
my $worksheetMETA = $workbook->add_worksheet('META');
$worksheetMETA->freeze_panes( 1, 0 );    # Freeze the first row
my $worksheetLineMETA = 1;

# OMIM worksheets
$tagsHash{'OMIMDOM'}{'label'} = 'OMIM_DOM' ;
$tagsHash{'OMIMDOM'}{'count'} = 0 ;
my $worksheetOMIMDOM = $workbook->add_worksheet('OMIM_DOM');
$worksheetOMIMDOM->freeze_panes( 1, 0 );    # Freeze the first row
my $worksheetLineOMIMDOM = 1;

# OMIM worksheets
$tagsHash{'OMIMREC'}{'label'} = 'OMIM_REC' ;
$tagsHash{'OMIMREC'}{'count'} = 0 ;
my $worksheetOMIMREC = $workbook->add_worksheet('OMIM_REC');
$worksheetOMIMREC->freeze_panes( 1, 0 );    # Freeze the first row
my $worksheetLineOMIMREC = 1;

#Worksheets initialization

my $worksheetHTZcompo;
my $worksheetAR;
my $worksheetSNPmumVsCNVdad ;
my $worksheetSNPdadVsCNVmum;
my $worksheetDENOVO;
my $worksheetCandidats;
#my $worksheetDELHMZ;

my $worksheetLineHTZcompo = 1 ;
my $worksheetLineAR = 1 ;
my $worksheetLineSNPmumVsCNVdad = 1 ;
my $worksheetLineSNPdadVsCNVmum = 1;
my $worksheetLineDENOVO = 1;
#my $worksheetLineCandidats;
#my $worksheetLineDELHMZ;

#create additionnal sheet in trio analysis
if (defined $trio){

	$tagsHash{'DENOVO'}{'label'} = 'DENOVO' ;
	$tagsHash{'DENOVO'}{'count'} = 0 ;
	$worksheetDENOVO = $workbook->add_worksheet('DENOVO');
	$worksheetDENOVO->freeze_panes( 1, 0 );    # Freeze the first row

	$tagsHash{'AUTOREC'}{'label'} = 'AR' ;
	$tagsHash{'AUTOREC'}{'count'} = 0 ;
	$worksheetAR = $workbook->add_worksheet('AR');
	$worksheetAR->freeze_panes( 1, 0 );    # Freeze the first row

	$tagsHash{'HTZcompo'}{'label'} = 'HTZ_compo' ;
	$tagsHash{'HTZcompo'}{'count'} = 0 ;
	$worksheetHTZcompo = $workbook->add_worksheet('HTZ_compo');
	$worksheetHTZcompo->freeze_panes( 1, 0 );    # Freeze the first row

	$tagsHash{'SNPmCNVp'}{'label'} = 'SNVmumVsCNVdad' ;
	$tagsHash{'SNPmCNVp'}{'count'} = 0 ;
	$worksheetSNPmumVsCNVdad = $workbook->add_worksheet('SNVmumVsCNVdad');
	$worksheetSNPmumVsCNVdad->freeze_panes( 1, 0 );    # Freeze the first row

	$tagsHash{'SNPpCNVm'}{'label'} = 'SNVdadVsCNVmum' ;
	$tagsHash{'SNPpCNVm'}{'count'} = 0 ;
	$worksheetSNPdadVsCNVmum = $workbook->add_worksheet('SNVdadVsCNVmum');
	$worksheetSNPdadVsCNVmum->freeze_panes( 1, 0 );    # Freeze the first row


	#$worksheetDELHMZ = $workbook->add_worksheet('DEL_HMZ');
	#$worksheetLineDELHMZ = 0;
	#$worksheetDELHMZ->freeze_panes( 1, 0 );    # Freeze the first row


}else{

	$tagsHash{'DENOVO'}{'label'} = 'DOM' ;
	$tagsHash{'DENOVO'}{'count'} = 0 ;
	$worksheetDENOVO = $workbook->add_worksheet('DOM');
	$worksheetDENOVO->freeze_panes( 1, 0 );    # Freeze the first row

	$tagsHash{'AUTOREC'}{'label'} = 'REC' ;
	$tagsHash{'AUTOREC'}{'count'} = 0 ;
	$worksheetAR = $workbook->add_worksheet('REC');
	$worksheetAR->freeze_panes( 1, 0 );    # Freeze the first row

	if ( @affectedArray){
		$tagsHash{'SNPmCNVp'}{'label'} = 'HTZ' ;
		$tagsHash{'SNPmCNVp'}{'count'} = 0 ;
		$worksheetSNPmumVsCNVdad = $workbook->add_worksheet('HTZ');

	}else{
		$tagsHash{'SNPmCNVp'}{'label'} = 'HMZonly' ;
		$tagsHash{'SNPmCNVp'}{'count'} = 0 ;
		$worksheetSNPmumVsCNVdad = $workbook->add_worksheet('HMZonly');
	}
	$worksheetSNPmumVsCNVdad->freeze_panes( 1, 0 );    # Freeze the first row

}




#get data from phenolyzer output (predicted_gene_score)
my $current_gene= "";
my $maxLine=0;
my $geneCounter=1;
if($phenolyzerFile ne ""){
	open(PHENO , "<$phenolyzerFile") or die("Cannot open phenolyzer file ".$phenolyzerFile) ;
	print  STDERR "Processing phenolyzer file ... \n" ;
	while( <PHENO> ){
		next if($_ =~/^Tuple number/);

		$phenolyzer_Line = $_;
		chomp $phenolyzer_Line;

		if($phenolyzer_Line=~/ID:/){

			#should write it for previous gene, not the current one $phenolyzerGene{$current_gene}{'comment'} = $maxLine." lines of features.\n";

			@phenolyzer_List = split( /\t/, $phenolyzer_Line);
			$current_gene = $phenolyzer_List[0];
			$phenolyzerGene{$current_gene}{'Raw'}= $phenolyzer_List[2];
			$phenolyzerGene{$current_gene}{'comment'}= $phenolyzer_List[1]."\n".$phenolyzer_List[3]."\n";
			$phenolyzerGene{$current_gene}{'normalized'}= $phenolyzer_List[3];
			$phenolyzerGene{$current_gene}{'rank'}= $geneCounter;
			$geneCounter ++;

			$maxLine=0;

		}else{
			#keep only OMIM or count nbr of lines
			$maxLine+=1;

		}
	}
	close(PHENO);
}

#custom VCF treatment
if($customVCF_File ne ""){

	open(CUSTOMVCF , "<$customVCF_File") or die("Cannot open customVCF file ".$customVCF_File) ;
	print  STDERR "Processing custom VCF file ... \n" ;
	while( <CUSTOMVCF> ){

  		$customVCF_Line = $_;

#############################################
##############   skip header
		next if ($customVCF_Line=~/^#/);

		chomp $customVCF_Line;
		@customVCF_List = split( /\t/, $customVCF_Line );

		#replace "spaces" by "_"
		$customVCF_List[7] =~ s/ /_/g;

		#build variant key as CHROM_POS_REF_ALT

		if (defined $customVCF_variant{$customVCF_List[0]."_".$customVCF_List[1]."_".$customVCF_List[3]."_".$customVCF_List[4]}){

			$customVCF_variant{$customVCF_List[0]."_".$customVCF_List[1]."_".$customVCF_List[3]."_".$customVCF_List[4]} .= ";".$customVCF_List[7];

		}else{

			$customVCF_variant{$customVCF_List[0]."_".$customVCF_List[1]."_".$customVCF_List[3]."_".$customVCF_List[4]} = $customVCF_List[7];
		}
	}

	close(CUSTOMVCF);
}

#Initialize Regex for filtering customVCF  (should be like that "wantedKey=" )
if ($filterCustomVCFRegex eq ""){
	$filterCustomVCFRegex = "found=";
}else{chomp $filterCustomVCFRegex ;}

# intersect VCF treatment
if($intersectVCF_File ne ""){

	open(INTERSECTVCF , "<$intersectVCF_File") or die("Cannot open intersectVCF file ".$intersectVCF_File) ;
	print  STDERR "Processing intersect VCF file ... \n" ;
	while( <INTERSECTVCF> ){

  		$intersectVCF_Line = $_;

#############################################
##############   skip header
		next if ($intersectVCF_Line=~/^#/);

		chomp $intersectVCF_Line;
		@intersectVCF_List = split( /\t/, $intersectVCF_Line );

		#replace "spaces" by "_"
		#$intersectVCF_List[7] =~ s/ /_/g;

		#build variant key as CHROM_POS_REF_ALT

		if (defined $intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}){

			#$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]} = "yes";

		}else{

			#$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]} = "yes";
			$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"exists"} = "yes";
			$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"seen"} = 0;
			$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"Phenotypes"} = "";
			$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"CLNSIG"} = "";
			$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"MPA_impact"} = "";
			
			
			########### Split INFOS #####################

			my %intersectInfo;
			my @infoList = split(';', $intersectVCF_List[7] );
			foreach my $info (@infoList){
				
				my @infoKeyValue = split('=', $info );
				if (scalar @infoKeyValue == 2){
					
					$infoKeyValue[1] =~ s/\\x3d/=/g;
					$infoKeyValue[1] =~ s/\\x3b/;/g;
					
					if ($infoKeyValue[0] eq "CLNSIG") {
						
						$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"CLNSIG"} = $infoKeyValue[1];
					
					}elsif( $infoKeyValue[0] eq "MPA_impact"){
						
						$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"MPA_impact"} = $infoKeyValue[1];
					
					}elsif( $infoKeyValue[0] =~ /^Phenotypes/){
						
						$intersectVCF_variant{$intersectVCF_List[0]."_".$intersectVCF_List[1]."_".$intersectVCF_List[3]."_".$intersectVCF_List[4]}{"Phenotypes"} = $infoKeyValue[1];

					}

				}
			}
		}
	}# end while
	close(INTERSECTVCF);
}








#create sheet for candidats
my $CANDID_TAG = "CANDIDATES";

my %candidWorksheetHash ;

if($candidates ne ""){
	open( CANDIDATS , "<$candidates")or die("Cannot open candidates file ".$candidates) ;
	print  STDERR "Processing candidates file ... \n" ;
	while( <CANDIDATS> ){
	  	$candidates_line = $_;
		chomp $candidates_line;

		if($candidates_line =~ m/#/ ){
			$candidates_line =~ s/#//g;
			$CANDID_TAG = "CANDID_".$candidates_line;
			$tagsHash{"CANDID_".$candidates_line}{'label'} = $candidates_line;
			$tagsHash{"CANDID_".$candidates_line}{'count'} = 0;

			#create 1 excel worksheet for each pathology (with # prefixed line)
			$candidWorksheetHash{$candidates_line}{'workbook'} = $workbook->add_worksheet($candidates_line);
			$candidWorksheetHash{$candidates_line}{'workbook'}->freeze_panes( 1, 0 );
			$candidWorksheetHash{$candidates_line}{'line'} = 0;

			next;
		}

		$candidateGene{$candidates_line} .= " ".$CANDID_TAG;


	}
	close(CANDIDATS);
	#$worksheetCandidats = $workbook->add_worksheet('Candidats');
	#$worksheetCandidats->freeze_panes( 1, 0 );    # Freeze the first row

	# create a generic "candidates" excel worksheet if no disease is given with #
	if( keys %candidWorksheetHash == 0 ){
		$candidWorksheetHash{'Candidats'}{'workbook'} = $workbook->add_worksheet('Candidates');
		$candidWorksheetHash{'Candidats'}{'workbook'}->freeze_panes( 1, 0 ); # Freeze the first row
		$candidWorksheetHash{'Candidats'}{'line'} = 0;

		$tagsHash{"CANDIDATES"}{'label'} = "Candidates";
		$tagsHash{"CANDIDATES"}{'count'} = 0;
	}
}


#get gene involved in CNV
if ($cnvGeneList ne ""){
	open( CNVGENES , "<$cnvGeneList")or die("Cannot open cnvGeneList file ".$cnvGeneList) ;
	print  STDERR "Processing CNV Gene file ... \n" ;
	while( <CNVGENES> ){
	  	$cnvGene_Line = $_;
		chomp $cnvGene_Line;
		@cnvGene_List = split( /\t/, $cnvGene_Line);
		$current_gene = $cnvGene_List[0];
		if (defined $cnvGene{$current_gene}){
				#nothing to do
		}else{
			$cnvGene{$current_gene} = "CNV : ".$current_gene;
		}

		if(defined $cnvGene_List[1]){
				$cnvGene{$current_gene} .= " => ".$cnvGene_List[1].";";
				chomp $cnvGene{$current_gene};
		}

	}
	close(CNVGENES);

}


#get favourite NM refGene
if($favouriteGeneRef ne ""){
	open( GENEREF , "<$favouriteGeneRef")or die("Cannot open your favourite GeneRef file ".$favouriteGeneRef) ;
	print  STDERR "Processing GeneRef file ... \n" ;
	while( <GENEREF> ){
	  	$geneRef_line = $_;
		chomp $geneRef_line;
		@geneRefArray = split( /\t/, $geneRef_line);
		$current_gene = $geneRefArray[0];
		if (defined $geneRef_gene{$current_gene}){
				#nothing to do
		}else{
			$geneRef_gene{$current_gene} = $current_gene;
		}
	}
	close(GENEREF);
}


#parse genemap2 file
if ( $genemap2_File ne ""  ){
	open(GENEMAP2 , "<$genemap2_File") or die("Cannot open genemap2 file ".$genemap2_File) ;
	print  STDERR "Processing genemap2 file ... \n" ;

	while( <GENEMAP2> ){

  		$genemap2_Line = $_;

		#skip header
		next if ($genemap2_Line=~/^#/);

		chomp $genemap2_Line;
		@genemap2_List = split( /\t/, $genemap2_Line );

		if (defined $genemap2_List[8]  && $genemap2_List[8] ne ""){
			if (defined $genemap2_variant{$genemap2_List[8]}){
				if (! defined $genemap2_List[12]){
					$genemap2_List[12] = "";
				}

				$genemap2_variant{$genemap2_List[8]} .= ";".$genemap2_List[12];

			}else{
				$genemap2_variant{$genemap2_List[8]} = $genemap2_List[12];
			}
		}
	}
	close(GENEMAP2);
}


#get mobidetails API key from achab script location or argument
if ($mdAPIkey eq ""){
	$mdAPIkey = dirname(__FILE__)."/MD.apikey";
}

open( MDAPIKEY , "<$mdAPIkey") or do {print "Didn't find any MoBiDetails APIkey file, expected: ".$mdAPIkey."\n"; $mdAPIkey = "";  } ;
#checkif file is empty
if (-z $mdAPIkey){
	$mdAPIkey = "";
	print "The MoBiDetails APIkey file: ".$mdAPIkey. " is empty. Please fill it";
}else{
	if ($mdAPIkey ne ""){
		print  STDERR "Processing MDAPIKEY file ... \n" ;
		while( <MDAPIKEY> ){
			$md_line = $_;
			chomp $md_line;
			if ($md_line eq ""){
				$mdAPIkey = "";
			}else{
				$mdAPIkey = "https://mobidetails.iurc.montp.inserm.fr/MD/api/variant/create_vcf_str?genome_version=".$build."&api_key=".$md_line."&vcf_str=";
			}
		}
	}
}
close(MDAPIKEY);



#Hash of 81 ACMG incidentalome genes secondary findings SF v3.2 according to  https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/
my %ACMGgene = ("ACTA2" =>1,"ACTC1" =>1,"ACVRL1" =>1,"APC" =>1,"APOB" =>1,"ATP7B" =>1,"BAG3" =>1,"BMPR1A" =>1,"BRCA1" =>1,"BRCA2" =>1,"BTD" =>1,"CACNA1S" =>1,"CALM1" =>1,"CALM2" =>1,"CALM3" =>1,"CASQ2" =>1,"COL3A1" =>1,"DES" =>1,"DSC2" =>1,"DSG2" =>1,"DSP" =>1,"ENG" =>1,"FBN1" =>1,"FLNC" =>1,"GAA" =>1,"GLA" =>1,"HFE" =>1,"HNF1A" =>1,"KCNH2" =>1,"KCNQ1" =>1,"LDLR" =>1,"LMNA" =>1,"MAX" =>1,"MEN1" =>1,"MLH1" =>1,"MSH2" =>1,"MSH6" =>1,"MUTYH" =>1,"MYBPC3" =>1,"MYH11" =>1,"MYH7" =>1,"MYL2" =>1,"MYL3" =>1,"NF2" =>1,"OTC" =>1,"PALB2" =>1,"PCSK9" =>1,"PKP2" =>1,"PMS2" =>1,"PRKAG2" =>1,"PTEN" =>1,"RB1" =>1,"RBM20" =>1,"RET" =>1,"RPE65" =>1,"RYR1" =>1,"RYR2" =>1,"SCN5A" =>1,"SDHAF2" =>1,"SDHB" =>1,"SDHC" =>1,"SDHD" =>1,"SMAD3" =>1,"SMAD4" =>1,"STK11" =>1,"TGFBR1" =>1,"TGFBR2" =>1,"TMEM127" =>1,"TMEM43" =>1,"TNNC1" =>1,"TNNI3" =>1,"TNNT2" =>1,"TP53" =>1,"TPM1" =>1,"TRDN" =>1,"TSC1" =>1,"TSC2" =>1,"TTN" =>1,"TTR" =>1,"VHL" =>1,"WT1" =>1);




#counter for shifting columns according to nbr of sample

my $cmpt = scalar @sampleList;

#Out-of-trio affected samples
my $NTaffectedCmpt = 0;
#Out-of-trio non-affected samples
my $NTnonAffectedCmpt = 0;

#dico for sample sorting (index / dad / mum / control)
my %dicoSamples ;

#dico for mozaic color association to sample
my %hashColor ;

#first: read VCF headers to get refGene or refGeneWithVer
#my $refGene = 'refGene';
#open( VCF , "<$incfile" )or die("Cannot open vcf file ".$incfile) ;
#while( <VCF> ){
#  	$current_line = $_;
#	if ($current_line=~/^##INFO=<ID=Func.refGeneWithVer,/o) {
#		$refGene = 'refGeneWithVer';
#		last;
#	}
#	elsif ($current_line=~/^##INFO=<ID=Func.refGene,/o) {last}
#}
#
my %dicoColumnNbr;

$dicoColumnNbr{'MPA_ranking'}=				0;	#+ comment MPA scores and related scores
$dicoColumnNbr{'MPA_impact'}=				1;	#+ comment MPA scores and related scores
$dicoColumnNbr{'Phenolyzer'}=				2;	#Phenolyzer raw score + comment Normalized score
$dicoColumnNbr{'Gene.'.$refGene}=				3;  #Gene Name + comment LOEUF / Function_description / tissue specificity
$dicoColumnNbr{'Phenotypes.'.$refGene}=			4;  #OMIM + comment Disease_description
$dicoColumnNbr{$gnomadGenomeColumn}=			5;	#Pop Freq + comment ethny
$dicoColumnNbr{$gnomadExomeColumn}=			6;	#as well
$dicoColumnNbr{'CLNSIG'}=				7;	#CLinvar
$dicoColumnNbr{'InterVar_automated'}=			8;	#+ comment ACMG status
$dicoColumnNbr{'SecondHit-CNV'}=			9;	#TODO
#$dicoColumnNbr{'Func.'.$refGene}=				10;	# + comment ExonicFunc / AAChange / GeneDetail



if (defined $trio){

		$dicoColumnNbr{'Genotype-'.$case}=		10;
		$dicoColumnNbr{'Genotype-'.$dad}=		11;
		$dicoColumnNbr{'Genotype-'.$mum}=		12;

		$dicoSamples{1}{'columnName'} = 'Genotype-'.$case ;
		$dicoSamples{2}{'columnName'} = 'Genotype-'.$dad ;
		$dicoSamples{3}{'columnName'} = 'Genotype-'.$mum ;

		#prepare mozaic colors for each sample at each column position , color is inherit by default
		$dicoSamples{1}{'columnNbr'} = 10;
		$dicoSamples{2}{'columnNbr'} = 11;
		$dicoSamples{3}{'columnNbr'} = 12;


		# TODO Add out-of-trio samples, affected samples first then non-affected samples
		 if ( scalar @sampleList > 3){
			if ( scalar  @affectedArray > 0){
				for( my $j = 0 ; $j < scalar @affectedArray; $j++){
					$NTaffectedCmpt++;
					if ($j eq $case or $j eq $dad or $j eq $mum){
						$NTaffectedCmpt--;
					}else{
						$dicoColumnNbr{'Genotype-'.$affectedArray[$j]}=		12+$NTaffectedCmpt;
						$dicoSamples{3+$NTaffectedCmpt}{'columnName'} = 'Genotype-'.$affectedArray[$j] ;
						$dicoSamples{3+$NTaffectedCmpt}{'columnNbr'} = 12+$NTaffectedCmpt ;

					}
				}
			}

			if ( scalar  @nonAffectedArray > 0){
				for( my $k = 0 ; $k < scalar @nonAffectedArray; $k++){
					$dicoColumnNbr{'Genotype-'.$nonAffectedArray[$k]}=		13+$NTaffectedCmpt+$k;
					$dicoSamples{4+$NTaffectedCmpt+$k}{'columnName'} = 'Genotype-'.$nonAffectedArray[$k] ;
					$dicoSamples{4+$NTaffectedCmpt+$k}{'columnNbr'} = 13+$NTaffectedCmpt+$k ;
					$NTnonAffectedCmpt++;
				}
			}
		}



}else{

	#TODO check how many affected samples in this non-trio sample

	if ( scalar  @affectedArray > 0){
			for( my $j = 0 ; $j < scalar @affectedArray; $j++){
				$NTaffectedCmpt++;
				$dicoColumnNbr{'Genotype-'.$affectedArray[$j]}=		10+$j;
				$dicoSamples{$j+1}{'columnName'} = 'Genotype-'.$affectedArray[$j] ;
				$dicoSamples{$j+1}{'columnNbr'} = 10+$j ;
			}
			if ( scalar  @nonAffectedArray > 0){
				for( my $k = 0 ; $k < scalar @nonAffectedArray; $k++){
					$dicoColumnNbr{'Genotype-'.$nonAffectedArray[$k]}=		10+$NTaffectedCmpt+$k;
					$dicoSamples{$NTaffectedCmpt+$k+1}{'columnName'} = 'Genotype-'.$nonAffectedArray[$k] ;
					$dicoSamples{$NTaffectedCmpt+$k+1}{'columnNbr'} = 10+$NTaffectedCmpt+$k ;
					$NTnonAffectedCmpt++;
				}
			}
	}else{
			for( my $i = 0 ; $i < scalar @sampleList; $i++){

				$dicoColumnNbr{'Genotype-'.$sampleList[$i]}=			10+$i;	# + comment qual / caller / DP AD AB
				$dicoSamples{$i+1}{'columnName'} = 'Genotype-'.$sampleList[$i] ;
				$dicoSamples{$i+1}{'columnNbr'} = 10+$i ;
			}
	}
}


$dicoColumnNbr{'#CHROMPOSREFALT'}=	10+$cmpt ;
#$dicoColumnNbr{'POS'}=		12+$cmpt ;
#$dicoColumnNbr{'ID'}=		13+$cmpt ;
#$dicoColumnNbr{'REF'}=		14+$cmpt ;
#$dicoColumnNbr{'ALT'}=		15+$cmpt ;
$dicoColumnNbr{'FILTER'}=	11+$cmpt ;

#Add custom Info in additionnal columns
my $lastColumn = 12+$cmpt;

# add case depth
if($case ne "" && defined $addCaseDepth){
	$dicoColumnNbr{'Case Depth'} = $lastColumn ;
	$lastColumn++;
}

# add case Allelic balance
if($case ne "" && defined $addCaseAB){
	$dicoColumnNbr{'Case AB'} = $lastColumn ;
	$lastColumn++;
}

if($customInfoList ne ""){
	chomp $customInfoList;
	@custInfList = split(/,/, $customInfoList);
	foreach my $customInfo (@custInfList){
		$dicoColumnNbr{$customInfo} = $lastColumn ;
		$lastColumn++;
	}
}


#add favorite gene references into a new column
if($favouriteGeneRef ne ""){
	$dicoColumnNbr{'geneRefs'} = $lastColumn ;
	$lastColumn++;
}



#custom VCF in last position
if($customVCF_File ne ""){
	$dicoColumnNbr{$filterCustomVCFRegex.'_customVCF'} = $lastColumn ;
	$lastColumn++;
	$dicoColumnNbr{'customVCFannotation'} = $lastColumn ;
	$lastColumn++;
}


#intersect VCF in last position
if($intersectVCF_File ne ""){
	$dicoColumnNbr{'intersectVCFannotation'} = $lastColumn ;
	$lastColumn++;
}


#TODO add a last column to flag newHope variants
if(defined $newHope){
	$dicoColumnNbr{'Catch_Class'} = $lastColumn ;
	$lastColumn++;
}





#Define column title order
my @columnTitles;
foreach my $key  (sort { $dicoColumnNbr{$a} <=> $dicoColumnNbr{$b} } keys %dicoColumnNbr)  {
	push @columnTitles,  $key;
	#DEBUG print STDERR $key."\n";
}
# fix gnomAD column names	
$columnTitles[5] = "gnomAD_Genome";
$columnTitles[6] = "gnomAD_Exome";


#final strings for comment
my $commentGenotype;
my $commentMPAscore;
my $commentGnomADExomeScore;
my $commentGnomADGenomeScore;
my $commentInterVar;
my $commentFunc;
my $commentPhenotype;
my $commentClinvar;

#define sorted arrays with score for comment
my @CommentMPA_score = ("MPA_ranking",
						"MPA_final_score",
						"MPA_impact",
						"MPA_adjusted",
						"MPA_available",
						"MPA_deleterious",
						"\n--- SPLICE ---",
						'dbscSNV_ADA_SCORE',
						'dbscSNV_RF_SCORE',
						'spliceai_filtered',
						#'DS_AG',
						#'DS_AL',
						#'DS_DG',
						#'DS_DL',
						"\n--- MISSENSE ---",
						'LRT_pred',
						'SIFT_pred',
						'FATHMM_pred',
						'MetaLR_pred',
						'MetaSVM_pred',
						'PROVEAN_pred',
						'Polyphen2_HDIV_pred',
						'Polyphen2_HVAR_pred',
						'MutationTaster_pred',
						'fathmm-MKL_coding_pred');

my $pLI_Comment = "pLI - the probability of being loss-of-function intolerant (intolerant of both heterozygous and homozygous lof variants)\npRec - the probability of being intolerant of homozygous, but not heterozygous lof variants\npNull - the probability of being tolerant of both heterozygous and homozygous lof variants";

my @CommentGnomadGenome;
if ($gnomadGenome_names ne ""){
	@CommentGnomadGenome = @gnomadGenome_List;
}else{
	@CommentGnomadGenome = ('gnomAD_genome_ALL',
                           'gnomAD_genome_AFR',
                           'gnomAD_genome_AMR',
                           'gnomAD_genome_ASJ',
                           'gnomAD_genome_EAS',
                           'gnomAD_genome_FIN',
                           'gnomAD_genome_NFE',
                           'gnomAD_genome_OTH');
}

my @CommentGnomadExome;
if ($gnomadExome_names ne ""){
	@CommentGnomadExome = @gnomadExome_List;
}else{
	@CommentGnomadExome = ('gnomAD_exome_ALL',
                          'gnomAD_exome_AFR',
                          'gnomAD_exome_AMR',
                          'gnomAD_exome_ASJ',
                          'gnomAD_exome_EAS',
                          'gnomAD_exome_FIN',
                          'gnomAD_exome_NFE',
                          'gnomAD_exome_OTH',
			  'gnomAD_exome_SAS');
}


my %CommentInterVar = (
'PVS1' => "Certain types of variants (e.g., nonsense, frameshift, canonical +- 1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where LOF is a known mechanism of diseas",
'PS1' => "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
    Example: Val->Leu caused by either G>C or G>T in the same codon",
'PS2' => "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history",
'PS3' => "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product",
'PS4' => "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls; OR>5 in all the gwas, the dataset is from gwasdb jjwanglab.org/gwasdb",
'PM1' => "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation",
'PM2' => "Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
'PM3' => "For recessive disorders, detected in trans with a pathogenic variant",
'PM4' => "Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants",
'PM5' => "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before;Example: Arg156His is pathogenic; now you observe Arg156Cys",
'PM6' => "Assumed de novo, but without confirmation of paternity and maternity",
'PP1' => "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease",
'PP2' => "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease",
'PP3' => "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) sfit for conservation, GERP++_RS for evolutionary, splicing impact from dbNSFP",
'PP4' => "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology",
'PP5' => "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation",
'BA1' => "BA1 Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
'BS1' => "Allele frequency is greater than expected for disorder (see Table 6) > 1% in ESP6500all ExAc? need to check more",
'BS2' => "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age, check ExAC_ALL",
'BS3' => "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing",
'BS4' => "Lack of segregation in affected members of a family",
'BP1' => "Missense variant in a gene for which primarily truncating variants are known to cause disease truncating:  stop_gain / frameshift deletion/  nonframshift deletion
	    We defined Protein truncating variants  (4) (table S1) as single-nucleotide variants (SNVs) predicted to introduce a premature stop codon or to disrupt a splice site, small insertions or deletions (indels) predicted to disrupt a transcript reading frame, and larger deletions ",
'BP2' => "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern",
'BP3' => "In-frame deletions/insertions in a repetitive region without a known function if the repetitive region is in the domain, this BP3 should not be applied.",
'BP4' => "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary,splicing impact, etc.)",
'BP5' => "Variant found in a case with an alternate molecular basis for disease.
check the genes whether are for mutilfactor disorder. The reviewers suggeset to disable the OMIM morbidmap for BP5",
'BP6' => "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation; Check the ClinVar column to see whether this is \"benign\".",
'BP7' => "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the
    splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved"
);


my @CommentFunc = (	'ExonicFunc.'.$refGene,
			'AAChange.'.$refGene,
			'GeneDetail.'.$refGene, 
			'ID',
			'Func.'.$refGene);


my @CommentPhenotype = ( 'Disease_description.'.$refGene);

my @CommentClinvar = (	'CLNREVSTAT',
			'CLNDN',
			'CLNALLELEID',
			'CLNDISDB');


#For HTML tooltip output
my %commentHash;
$commentHash{'0'}='commentMPAscore';
$commentHash{'1'}='commentFunc';
$commentHash{'2'}='commentPhenolyzer';
$commentHash{'3'}='commentpLI';
$commentHash{'4'}='commentPhenotype';
$commentHash{'5'}='commentGnomADgenome';
$commentHash{'6'}='commentGnomADexome';
$commentHash{'7'}='commentClinvar';
$commentHash{'8'}='commentInterVar';
$commentHash{'11'}='commentGenotype';






#########FILLING COLUMN TITLES FOR SHEETS
$worksheet->write_row( 0, 0, \@columnTitles );
if (defined $hideACMG){
	$worksheetACMG->write( 0, 0, "ACMG lines are hidden.");
}else{
	$worksheetACMG->write_row( 0, 0, \@columnTitles );
}
$worksheetMETA->write( 0, 0, "METADATA" );
$worksheetOMIMDOM->write_row( 0, 0, \@columnTitles );
$worksheetOMIMREC->write_row( 0, 0, \@columnTitles );


#write comment for pLI => NOW LOEUF is used
$worksheet->write_comment( 0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3 );
unless(defined $hideACMG){ $worksheetACMG->write_comment( 0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3  )};


#FILLING COLUMN TITLES FOR TRIO SHEETS OR AFFECTED OR STRANGERS
if (defined $trio){
	$worksheetHTZcompo->write_row( 0, 0, \@columnTitles );
	$worksheetSNPdadVsCNVmum->write_row( 0, 0, \@columnTitles );

	#write pLI - LOEUF comment
	$worksheetHTZcompo->write_comment(0,$dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3);
	$worksheetSNPdadVsCNVmum->write_comment(0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3);

}

$worksheetAR->write_row( 0, 0, \@columnTitles );
$worksheetDENOVO->write_row( 0, 0, \@columnTitles );
$worksheetSNPmumVsCNVdad->write_row( 0, 0, \@columnTitles );

#write pLI - LOEUF comment
$worksheetAR->write_comment(0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3);
$worksheetDENOVO->write_comment( 0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3);
$worksheetSNPmumVsCNVdad->write_comment(0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3);



#FILLING COLUMN TITLES FOR CANDIDATES SHEET

if($candidates ne ""){
	foreach my $patho (keys %candidWorksheetHash){


		$candidWorksheetHash{$patho}{'workbook'}->write_row( 0, 0, \@columnTitles );
		$candidWorksheetHash{$patho}{'workbook'}->write_comment(0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3 );
		$candidWorksheetHash{$patho}{'line'} = 1 ;

		#$worksheetCandidats->write_row( 0, 0, \@columnTitles );
		#$worksheetCandidats->write_comment(0, $dicoColumnNbr{'Gene.'.$refGene}, $pLI_Comment,  x_scale => 3 );
	}
}


####################################################################
#
#
#
#

my %dicoGeneForHTZcompo;
my $previousGene ="";
my $filterBool;
$dicoGeneForHTZcompo{$previousGene}{'ok'}=0;
$dicoGeneForHTZcompo{$previousGene}{'cnt'}=0;




#############################################
##################   Start parsing VCF

open( VCF , "<$incfile" )or die("Cannot open vcf file ".$incfile) ;


while( <VCF> ){
  	$current_line = $_;
	$count++;

#############################################
##############   skip header
	next if ($current_line=~/^##/);

	chomp $current_line;
	@line = split( /\t/, $current_line );

	#DEBUG print STDERR $dicoColumnNbr{'Gene.'.$refGene}."\n";
 


#############################################
##############   Treatment for First line to create header of the output

	if ( $line[0] eq "#CHROM" )   {



		#############CHECK IF $nbrSample == $cmpt else exit error nbr sample

	    #find correct index for samples of the family
		#for each sample position
		for( my $sampleIndex = 9 ; $sampleIndex < scalar @line; $sampleIndex++){

			#for each final position for sample
			foreach my $finCol (keys %dicoSamples){
    	    #DEBUG

				if ($dicoSamples{$finCol}{'columnName'} eq "Genotype-".$line[$sampleIndex] ){
					$dicoSamples{$finCol}{'columnIndex'} =  $sampleIndex;
					last;
				}
			}

#			foreach my $name (@sampleList)
				#if($line[$sampleIndex]

		}



		next;

#############################################
##############################
##########  start to compute variant lines

	}else {



		#initialise final printable string
		@finalSortData = ("");
		$mozaicSamples = "";

		my $alt="";
		my $ref="";

		#Split line with tab

		#DEBUG		print $current_line,"\n";

		#filling output line with classical first vcf columns
		$finalSortData[$dicoColumnNbr{'#CHROMPOSREFALT'}]=	$line[0]."-".$line[1]."-".$line[3]."-".$line[4];
		#$finalSortData[$dicoColumnNbr{'POS'}]=		$line[1];
		#$finalSortData[$dicoColumnNbr{'ID'}]=		$line[2];
		#$finalSortData[$dicoColumnNbr{'REF'}]=		$line[3];
		#$finalSortData[$dicoColumnNbr{'ALT'}]=		$line[4];
		$finalSortData[$dicoColumnNbr{'FILTER'}]=	$line[6];




#############################################
########### Split INFOS #####################

		my %dicoInfo;
		#$line[7] =~ s/\\x3d/=/g;
		#$line[7] =~ s/\\x3b/;/g;
		my @infoList = split(';', $line[7] );
		foreach my $info (@infoList){
			my @infoKeyValue = split('=', $info );
			if (scalar @infoKeyValue == 2){

				$infoKeyValue[1] =~ s/\\x3d/=/g;
				$infoKeyValue[1] =~ s/\\x3b/;/g;

				$dicoInfo{$infoKeyValue[0]} = $infoKeyValue[1];
				#DEBUG
				#print $infoKeyValue[1]."\n";
			}
		}
		
		# add ID and FILTER to the dicoInfo
		$dicoInfo{'ID'} = $line[2];
		$dicoInfo{'FILTER'} = $line[6];


#DEBUG
#print Dumper(\%dicoInfo);

		#perform ID monitoring

		if ($IDSNP ne ""){
			if (defined $hashIDSNP{$finalSortData[$dicoColumnNbr{'ID'}]}){

				foreach my $finalcol ( sort {$a <=> $b}  (keys %dicoSamples) ) {

					my @genotype = split(':', $line[$dicoSamples{$finalcol}{'columnIndex'}] );


					my %formatIndexID;
					my @callerFormatID = split(':' , $line[8]);
					for (my $z = 0; $z < scalar @callerFormatID; $z++){
						$formatIndexID{$callerFormatID[$z]} = $z;
					}

					if(defined $hashIDSNP{'samples'}  ){
						#nothing to do
					}else{
						$hashIDSNP{'samples'} .=  substr($dicoSamples{$finalcol}{'columnName'},9,length($dicoSamples{$finalcol}{'columnName'})-9) ."\t";
					}
					$hashIDSNP{$finalSortData[$dicoColumnNbr{'ID'}]} .= $genotype[$formatIndexID{'GT'}] ."\t";


				}
			}

		}


		#select only x% pop freq
		#Use pop freq threshold as an input parameter (default = 1%)
		next if(( $dicoInfo{$gnomadGenomeColumn} ne ".") && ($dicoInfo{$gnomadGenomeColumn} > $popFreqThr));

		#convert gnomad freq "." to zero
		if( $dicoInfo{$gnomadGenomeColumn} eq "."){
			$dicoInfo{$gnomadGenomeColumn} = 0;
		}
		if( $dicoInfo{$gnomadExomeColumn} eq "."){
			$dicoInfo{$gnomadExomeColumn} = 0;
		}

		#FILTERING according to newHope option and filterList option
		$filterBool = 0;

		#switch ($finalSortData[$dicoColumnNbr{'FILTER'}]){
		switch ($dicoInfo{'FILTER'}){
			case (\@filterArray) {$filterBool=0}
			else {$filterBool=1}
		}


		if(defined $newHope){
			#Keep only NON PASS or PASS + MPA ranking = 8
			#next if ($finalSortData[$dicoColumnNbr{'FILTER'}] eq "PASS" && $dicoInfo{'MPA_ranking'} < 8);
			#switch ($finalSortData[$dicoColumnNbr{'FILTER'}]){
			#	case (\@filterArray) { $filterBool=1 };
			#}
			#next if($filterBool == 1);
			#next if($dicoInfo{'MPA_ranking'} < 8 );

			if ($filterBool == 1 or $dicoInfo{'MPA_ranking'} == 10){
				$dicoInfo{'Catch_Class'} = "New_Hope";
			}else{
				$dicoInfo{'Catch_Class'} = "Main";
			}

		}else{

			#remove NON PASS variant and remove MPA_Ranking = 10
			next if ($filterBool == 1);
			next if( $dicoInfo{'MPA_ranking'} == 10);

			#next if ($finalSortData[$dicoColumnNbr{'FILTER'}] ne "PASS");
		}




		#filling output line, check if INFO exists in the VCF
		foreach my $keys (sort keys %dicoColumnNbr){

#			print "keysListe\t#".$keys."#\n";

			if (defined $dicoInfo{$keys}){

				$finalSortData[$dicoColumnNbr{$keys}] = $dicoInfo{$keys};
				#DEBUG
				#print "finalSort\t".$finalSortData[$dicoColumnNbr{$keys}]."\n";
				#print "dicoInfo\t".$dicoInfo{$keys}."\n";
				#print "keys\t".$keys."\n";
			}else{
				#check if custom INFO exists in VCF or gnomad_genome or gnomad_exome names
				if($dicoColumnNbr{$keys} > (16+$cmpt) || $dicoColumnNbr{$keys} == 5 || $dicoColumnNbr{$keys} == 6 ){
					$finalSortData[$dicoColumnNbr{$keys}] = "INFO not found";
				}
			}
		}


		#split multiple gene names
		@geneListTemp = split(';', $finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] );

		#uniq genes names
		@geneList = do { my %seen; grep { !$seen{$_}++ } @geneListTemp };

		#reset gene name
		$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] = "";
        
		#uniq gene name in output
		foreach my $geneName (@geneList){
			$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] .= $geneName.";";
			
			#try to rescue OMIM annotation in multiple gene lines
			if (scalar @geneListTemp > 1){
				if (defined $dicoInfo{'Phenotypes.'.$refGene} ){
					if ($dicoInfo{'Phenotypes.'.$refGene} eq "." ){
						if (defined $genemap2_variant{$geneName} ){
							if ( $genemap2_variant{$geneName} ne ""){
								$finalSortData[$dicoColumnNbr{'Phenotypes.'.$refGene}] .=  $genemap2_variant{$geneName}.";";
								$dicoInfo{'Phenotypes.'.$refGene} .= $genemap2_variant{$geneName}.";";
							}
						}
					}
				}
			}
        }
        # remove last ";"
        chop($finalSortData[$dicoColumnNbr{'Gene.'.$refGene}]);


		#Phenolyzer Column
		if($phenolyzerFile ne ""){

			#@geneList = split(';', $finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] );

			my $phenoScoreMax=0;
			foreach my $geneName (@geneList){
				#if (defined $phenolyzerGene{$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}]} )
				if (defined $phenolyzerGene{$geneName} ){
					if( ! defined $finalSortData[$dicoColumnNbr{'Phenolyzer'}]){
						$finalSortData[$dicoColumnNbr{'Phenolyzer'}] = $phenolyzerGene{$geneName}{'Raw'};
					}elsif( $finalSortData[$dicoColumnNbr{'Phenolyzer'}] eq "." || ( $phenolyzerGene{$geneName}{'Raw'} ne "." &&   $phenolyzerGene{$geneName}{'Raw'} > $finalSortData[$dicoColumnNbr{'Phenolyzer'}])){
						$finalSortData[$dicoColumnNbr{'Phenolyzer'}] = $phenolyzerGene{$geneName}{'Raw'};

						if($phenoScoreMax < $phenolyzerGene{$geneName}{'Raw'}){
							$phenoScoreMax = $phenolyzerGene{$geneName}{'Raw'};
						}
					}

				}else{
					$finalSortData[$dicoColumnNbr{'Phenolyzer'}] = ".";
				}

			}

			#refine MPA_rank  with phenolyzer normalized score
			$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += (0.001-($phenoScoreMax/1000 )) ;

		}else{
			$finalSortData[$dicoColumnNbr{'Phenolyzer'}] = ".";
		}
#
		#CNV GENES
		if($cnvGeneList ne ""){

			#@geneList = split(';', $finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] );
			foreach my $geneName (@geneList){
				#print $geneName."\n";
				if (defined $cnvGene{$geneName} ){
					#print $geneName."toto\n";
					$finalSortData[$dicoColumnNbr{'SecondHit-CNV'}] .= $cnvGene{$geneName}."_";
					#print $finalSortData[$dicoColumnNbr{'SecondHit-CNV'}]."\n";
				}
			}
		}





		#MPA COMMENT
		#create string with array
		$commentMPAscore = "";
		foreach my $keys (@CommentMPA_score){
			if (defined $dicoInfo{$keys} ){
				if($keys eq "spliceai_filtered"){
					my @dicoSplice = split(';', $dicoInfo{$keys} );
					if (scalar @dicoSplice > 2){
						foreach my $spliceData (@dicoSplice){
							if ($spliceData=~/^DS_/){
								$commentMPAscore .= $keys."\t ".$spliceData."\n";
							}
						}
					}else{
						$commentMPAscore .= $keys."\t= ".$dicoInfo{$keys}."\n";
					}
				}else{
					$commentMPAscore .= $keys."\t= ".$dicoInfo{$keys}."\n";
				}
			}else{
				$commentMPAscore .= $keys."\n";
			}
		}

		#refine MPA_rank  with pLI - LOEUF
		if(($finalSortData[$dicoColumnNbr{'MPA_ranking'}] >= 5 && $finalSortData[$dicoColumnNbr{'MPA_ranking'}] < 6 )|| ($finalSortData[$dicoColumnNbr{'MPA_ranking'}] >= 7 && $finalSortData[$dicoColumnNbr{'MPA_ranking'}] < 8 ) || ($finalSortData[$dicoColumnNbr{'MPA_ranking'}] >= 9 && $finalSortData[$dicoColumnNbr{'MPA_ranking'}] < 10 )  ){
			#$format_pLI = $workbook->add_format(bg_color => $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'});

            #LOEUF refinement





			#if(defined $dicoInfo{'Missense_Z_score.'.$refGene} && $dicoInfo{'Missense_Z_score.'.$refGene} ne "." ){
			if(defined $dicoInfo{'oe_mis_upper.'.$refGene} && $dicoInfo{'oe_mis_upper.'.$refGene} ne "." ){
  				#$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += (0.0001-((($dicoInfo{"Missense_Z_score.".$refGene}+8.64)/22.52)/10000 )) ;



                #oe_mis_upper  MAX=    MIN=

                $finalSortData[$dicoColumnNbr{'MPA_ranking'}] += $dicoInfo{"oe_mis_upper.".$refGene}/20000 ;


			}else{
				$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += 0.0001;
			}

			#add MPA_final_score before MPA_impact
			$finalSortData[$dicoColumnNbr{'MPA_impact'}] = $dicoInfo{"MPA_deleterious"}."_".$finalSortData[$dicoColumnNbr{'MPA_impact'}];


			#refine MPA_rank for rank 7 missense with MPA final score
			$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += ((10-$dicoInfo{"MPA_final_score"})/100);
			#print "final_score   :   ".$finalSortData[$dicoColumnNbr{'MPA_ranking'}]."\t".((10-$dicoInfo{"MPA_final_score"})/100)."\t".$dicoInfo{"MPA_final_score"}."\n";




		}elsif(defined $dicoInfo{"oe_lof_upper.".$refGene} && $dicoInfo{"oe_lof_upper.".$refGene} ne "." ){

            #LOEUF  MAX=1.996    MIN=0.03

           #clean double LOEUF
            $dicoInfo{"oe_lof_upper.".$refGene} =~ s/;\.//g;
            $finalSortData[$dicoColumnNbr{'MPA_ranking'}] += $dicoInfo{"oe_lof_upper.".$refGene}/20000 ;


            #$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += (0.0001-(($dicoInfo{"pLi.".$refGene}/10000 +  $dicoInfo{"pRec.".$refGene}/100000 + $dicoInfo{"pNull.".$refGene}/1000000))) ;
					#print $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."\n";


		}else{
			$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += 0.0001;
		}



		#Penalization of MPA score=7 or 9  to be after at least 9.06 score
		#no need since MPA v1.1.0

		#if($dicoInfo{"MPA_ranking"} == 7 ){
		#	$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += 2.061;
		#}elsif( $dicoInfo{"MPA_ranking"} == 9){
		#	$finalSortData[$dicoColumnNbr{'MPA_ranking'}] += 1.062;
		#}



		#Initialize list of variant tags
		$worksheetTAG = "";

        #Classify OMIM dominant and/or recessive gene variant
        if (defined $dicoInfo{'Phenotypes.'.$refGene} ){

            if($dicoInfo{'Phenotypes.'.$refGene} =~ m/dominant/ ){
                $worksheetTAG .= " OMIMDOM";
				$tagsHash{"OMIMDOM"}{'count'} ++;
            }

            if($dicoInfo{'Phenotypes.'.$refGene} =~ m/recessive/ ){
                $worksheetTAG .= " OMIMREC";
				$tagsHash{"OMIMREC"}{'count'} ++;
            }

        }



		#GNOMAD_EXOME COMMENT
		#create string with array
		$commentGnomADExomeScore = "";
		foreach my $keys (@CommentGnomadExome){
			if (defined $dicoInfo{$keys} ){
				$commentGnomADExomeScore .= $keys."\t= ".$dicoInfo{$keys}."\n";
			}
		}

		#GNOMAD_GENOME COMMENT
		#create string with array
		$commentGnomADGenomeScore = "";
		foreach my $keys (@CommentGnomadGenome){
			if (defined $dicoInfo{$keys} ){
				$commentGnomADGenomeScore .= $keys."\t= ".$dicoInfo{$keys}."\n";
			}
		}

		#INTERVAR COMMENT
		#create string with hash
		$commentInterVar = "";
		foreach my $keys (keys %CommentInterVar){
			if (defined $dicoInfo{$keys} && $dicoInfo{$keys} ne "." && $dicoInfo{$keys} ne "0"){
				$commentInterVar .= $keys."\t= ".$dicoInfo{$keys}."\n".$CommentInterVar{$keys}."\n\n";
			}
		}



		#FUNCTION REFGENE COMMENT
		#create string with array
		$commentFunc = "";
		foreach my $keys (@CommentFunc){
			if (defined $dicoInfo{$keys} ){
				$dicoInfo{$keys} =~ s/[;,]/\n /g;
				$commentFunc .= $keys.":\n ".$dicoInfo{$keys}."\n\n";
			}
		}

		#TODO check here if transcript reference is present in this comment and extract data in a new column
		# check among favourite NM references
		if ($favouriteGeneRef ne ""){
			#extract NM_blablah reference and recycling geneRefArray
			if (@geneRefArray = $commentFunc =~ m/(.+(NM_\d+):.+)/g){
				if (@geneRefArray){
					for( my $match = 0 ; $match < scalar @geneRefArray; $match +=2){
						if (defined $geneRef_gene{$geneRefArray[$match+1]}){
							$finalSortData[$dicoColumnNbr{'geneRefs'}] .= $geneRefArray[$match].";";
						}
					}
				}
			}
		}



		#PHENOTYPES REFGENE COMMENT (OMIM)
		#create string with array
		$commentPhenotype = "";
		foreach my $keys (@CommentPhenotype){
			if (defined $dicoInfo{$keys} ){

				$dicoInfo{$keys} =~ s/DISEASE:_/\n\nDISEASE:_/g;
				$commentPhenotype .= $keys.":\n ".$dicoInfo{$keys}."\n\n";
			}
		}


		#CLINVAR COMMENT (CLNSIG)
		#create string with array
		$commentClinvar = "";
		foreach my $keys (@CommentClinvar){
			if (defined $dicoInfo{$keys} ){
				$commentClinvar .= $keys.":\n ".$dicoInfo{$keys}."\n\n";
			}
		}



############################################
#############	Check FORMAT related to caller
		#
		my %formatIndex;
		my @callerFormat = split(':' , $line[8]);
		for (my $z = 0; $z < scalar @callerFormat; $z++){
			$formatIndex{$callerFormat[$z]} = $z;
		}



		#		GT:AD:DP:GQ:PL (haplotype caller)
		#		GT:DP:GQ  => multiallelic line , vcf not splitted => should be done before, STOP RUN?
		#		GT:GOF:GQ:NR:NV:PL (platyplus caller)
		#		GT:DP:RO:QR:AO:QA:GL (freebayes)
		#		GT:DP:AF (seqNext)
		#
		$caller = "";
		if(defined $formatIndex{'VAF'}){
			$caller = "DeepVariant";
		}elsif(defined $formatIndex{'AD'}){
			$caller = "GATK";
		}elsif(defined $formatIndex{'NR'}){
			$caller = "platypus";
		}elsif(defined $formatIndex{'AO'}){
			$caller = "freebayes";
		}elsif(defined $formatIndex{'AF'} ){
			# "GT:DP:AF"
			#SeqNext like format
			$caller = "other _ GT:DP:AF";

		}elsif(defined $formatIndex{'DP'}){
			$caller = "other _ GT:DP";
			#print STDERR "Multi-allelic line detection. Please split the vcf file in order to get 1 allele by line\n";
			#print STDERR $current_line ."\n";
			#exit 1;



		}else{
			print STDERR "The Format of the Caller used for this line is unknown. Processing is a risky business. This line won't be processed.\n";
			print STDERR $current_line ."\n";
			$caller = "unknown";
			next;
			#exit 1;
		}




		#genotype concatenation for easy hereditary status
		$familyGenotype = "_";
		$commentGenotype = "CALLER = ".$caller."\t QUALITY = ".$line[5]."\n\n";

		#DEBUG print STDERR "commentgeno     :     ".$commentGenotype."\n";

#############################################################################
#########FILL HASH STRUCTURE FOR FINAL SORT AND OUTPUT, according to rank

		#concatenate chrom_POS_REF_ALT to get variant ID
		$variantID = $line[0]."_".$line[1]."_".$line[3]."_".$line[4]."_".$count;
		#$variantID = $line[0]."_".$line[1]."_".$line[3]."_".$line[4]."_".$caller;


		#CHECK IF variant is in customVCF
		if($customVCF_File ne ""){

			if( defined $customVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}){
				$finalSortData[$dicoColumnNbr{'customVCFannotation'}] = $customVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]};

				#if($filterCustomVCF ne "" && $finalSortData[$dicoColumnNbr{'customVCFannotation'}] =~ m/$filterCustomVCFRegex(\d*)/){
				if($finalSortData[$dicoColumnNbr{'customVCFannotation'}] =~ m/$filterCustomVCFRegex(\d*)/){
				
					#Penalize variant if "found=*" is greater than filterCustomVCF option
					if($filterCustomVCF ne "" && $1 >= $filterCustomVCF){
						$finalSortData[$dicoColumnNbr{'MPA_ranking'}]   += 100;
					}
						
					#add value in a new column
					if (defined $addCustomVCFRegex ){
						$finalSortData[$dicoColumnNbr{$filterCustomVCFRegex.'_customVCF'}] = $1;
					}

				}else{
					#add absent value in a new column :  -1 is regex pattern not found
					if (defined $addCustomVCFRegex ){
						$finalSortData[$dicoColumnNbr{$filterCustomVCFRegex.'_customVCF'}] = "-1";
					}
				}	
			}else{
				$finalSortData[$dicoColumnNbr{$filterCustomVCFRegex.'_customVCF'}] = "0";
				$finalSortData[$dicoColumnNbr{'customVCFannotation'}] = ".";
			}
		}

		#CHECK IF variant is in intersectVCF
		if($intersectVCF_File ne ""){

			if( defined $intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"exists"}){
				$finalSortData[$dicoColumnNbr{'intersectVCFannotation'}] = "yes";
				$intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"seen"} ++ ;
				
				if ($dicoInfo{"CLNSIG"} ne  $intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"CLNSIG"} ){
					$finalSortData[$dicoColumnNbr{'intersectVCFannotation'}] .= ";CLNSIG:".$intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"CLNSIG"}; 
				}	
				if ($dicoInfo{"Phenotypes.".$refGene} ne  $intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"Phenotypes"} ){
					$finalSortData[$dicoColumnNbr{'intersectVCFannotation'}] .= ";Phenotypes:".$intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"Phenotypes"}; 
				}	
				if ($dicoInfo{"MPA_impact"} ne  $intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"MPA_impact"} ){
					$finalSortData[$dicoColumnNbr{'intersectVCFannotation'}] .= ";MPA_impact:".$intersectVCF_variant{$line[0]."_".$line[1]."_".$line[3]."_".$line[4]}{"MPA_impact"}; 
				}	

			}else{
				$finalSortData[$dicoColumnNbr{'intersectVCFannotation'}] = "no";
			}
		}




############################################
#############   Parse Genotypes
		#

		#for each sample sort by sample wanted
		foreach my $finalcol ( sort {$a <=> $b}  (keys %dicoSamples) ) {

			#DEBUG print "tata\t".$finalcol."\n";
			#DEBUG	print $line[$dicoSamples{$finalcol}{'columnIndex'}]."\n";

				my @genotype = split(':', $line[$dicoSamples{$finalcol}{'columnIndex'}] );
				#my $genotype =  $line[$dicoSamples{$finalcol}{'columnIndex'}];

                my $DP; #total Depth

                if (defined $formatIndex{'DP'}){
				    $DP = $genotype[$formatIndex{'DP'}];
                }


				my $adalt;	#Alternative Allelic Depth
				my $adref;	#Reference Allelic Depth
				my $AB;		#Allelic balancy
				my $AD;		#Final Allelic Depth


				#if (scalar @genotype > 1 && $caller ne "")
				if ($caller ne "unknown"){

					if(	($caller eq "GATK" ) || ($caller eq "DeepVariant")){

						#check if variant is not called
						if ($DP eq "."){
							$DP = 0;
							$AD = "0,0";

						}else{
							$AD = $genotype[$formatIndex{'AD'}];
						}

					}elsif($caller eq "platypus"){

						if($genotype[$formatIndex{'NR'}] =~ m/,/){
							my @genotype_DPsplit = split(',', $genotype[$formatIndex{'NR'}]);
							my @genotype_ADsplit = split(',', $genotype[$formatIndex{'NV'}]);
							$DP = $genotype_DPsplit[0];
							$AD = ($genotype_DPsplit[0] - $genotype_ADsplit[0]);
							$AD .= ",".$genotype_ADsplit[0];

						}else{
							$DP = $genotype[$formatIndex{'NR'}];
							$AD = ($genotype[$formatIndex{'NR'}] - $genotype[$formatIndex{'NV'}]);
							$AD .= ",".$genotype[$formatIndex{'NV'}];
						}
					}elsif($caller eq "other _ GT:DP"){

						$AD = 0;
						$AD .= ",0";

					}elsif($caller eq "other _ GT:DP:AF"){
						$AD = ($DP-int($DP*$genotype[$formatIndex{'AF'}])) . "," . int($DP*$genotype[$formatIndex{'AF'}]);

					}elsif($caller eq "freebayes"){
						$AD = $genotype[$formatIndex{'RO'}];
						$AD .= ",".$genotype[$formatIndex{'AO'}];
					}

					#DEBUG
					#print $genotype[2]."\n";


					#split allelic depth
					my @tabAD = split( ',',$AD);

					#print "\ntabAD\t",split( ',',$AD),"\n";

					if ( scalar @tabAD > 1 ){
						$adref = $tabAD[0];
						$adalt = $tabAD[1];
						my $totalAD = $adref;



						for (my $j = 1; $j < scalar @tabAD; $j++){
							$totalAD += $tabAD[$j];
						}

						if ($totalAD == 0){
							$AB = 0;
						}else{
							for (my $j = 1; $j < scalar @tabAD; $j++){

								$AB .= substr(($tabAD[$j]/ $totalAD),0,5);
								$AB .= ",";

							}


							$AB= substr $AB, 0 , ((length $AB)-1);


						}

					}else {
						$adref = 0;
						$adalt= 0;
						$AB = 0;
					}


				}else {  # caller unknown           @genotype length < 1
					$adref = 0;
					$adalt= 0;
					$AB = 0;
					$DP = $line[8];
					$AD = $line[$dicoSamples{$finalcol}{'columnIndex'}];
				}



				#DEBUG print STDERR "indexSample\t".$dicoSamples{$finalcol}{'columnIndex'}."\n";

				#put the genotype and comments info into string
				#convert "1/0" genotype to "0/1" format
				if($genotype[$formatIndex{'GT'}] eq "1/0"){
					$genotype[$formatIndex{'GT'}] = "0/1";
				}

				#$commentGenotype .=  $dicoSamples{$finalcol}{'columnName'}."\t -\t ".$genotype[$formatIndex{'GT'}]."\nDP = ".$DP."\t AD = ".$AD."\t AB = ".$AB."\n\n";



				#record mozaic status of samples and (TODO) low cov for 1/1 genotypes
				if(($genotype[$formatIndex{'GT'}] eq "0/1" && $AB < $mozaicRate) or ($genotype[$formatIndex{'GT'}] eq "1/1" && $adalt < $mozaicDP     )){

					$mozaicSamples  .= $dicoSamples{$finalcol}{'columnName'}.";";

					#penalty to MPA ranking if trio and mozaic for the index case
					if(defined $trio && $dicoSamples{$finalcol}{'columnName'} eq "Genotype-".$case){
						$finalSortData[$dicoColumnNbr{'MPA_ranking'}] 	+= 0.1;

						#penalty to low covered ALT base
						if($adalt < $mozaicDP){
							$finalSortData[$dicoColumnNbr{'MPA_ranking'}]   += 0.1;
						}
					}

					if($genotype[$formatIndex{'GT'}] eq "1/1"){
						$mozaicSamples  .= 'cyan'.";";
						$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'cyan';

					}elsif($adalt < $mozaicDP){
						$mozaicSamples  .= 'purple'.";";
						$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'purple';
					}else{
						$mozaicSamples  .= 'pink'.";";
						$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'pink';
					}


				}else{
					$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'inherit';
				}
			
			
				# POOL samples treatment, change genotype 0/0 to 0/1 if ALT depth > 1 , give yellow color to the changed sample genotype
				if ($genotype[$formatIndex{'GT'}] eq "0/0" && $adalt >= 1){

					if (defined $hashPooledSamples{substr($dicoSamples{$finalcol}{'columnName'},9,length($dicoSamples{$finalcol}{'columnName'})-9) }){
						$mozaicSamples  .= $dicoSamples{$finalcol}{'columnName'}.";";
						$mozaicSamples  .= 'yellow'.";";
						$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'yellow';
						$genotype[$formatIndex{'GT'}] = "0/1";
						$commentGenotype .=  $dicoSamples{$finalcol}{'columnName'}."\t -\t ".$genotype[$formatIndex{'GT'}]." (recomputed 0/0)\nDP = ".$DP."\t AD = ".$AD."\t AB = ".$AB."\n\n";
						#penalize if recomputed pool
						if($dicoSamples{$finalcol}{'columnName'} eq "Genotype-".$case){
							$finalSortData[$dicoColumnNbr{'MPA_ranking'}] 	+= 0.21;
						}
					}else{
						$commentGenotype .=  $dicoSamples{$finalcol}{'columnName'}."\t -\t ".$genotype[$formatIndex{'GT'}]."\nDP = ".$DP."\t AD = ".$AD."\t AB = ".$AB."\n\n";
						$hashColor{$dicoSamples{$finalcol}{'columnNbr'}} = 'inherit';
					}	
				}else{
					#compose comment
					$commentGenotype .=  $dicoSamples{$finalcol}{'columnName'}."\t -\t ".$genotype[$formatIndex{'GT'}]."\nDP = ".$DP."\t AD = ".$AD."\t AB = ".$AB."\n\n";
				}
				
				# add depth (DP) of the Case in supplementary column
				if (defined $addCaseDepth && $dicoSamples{$finalcol}{'columnName'} eq "Genotype-".$case){
					$finalSortData[$dicoColumnNbr{'Case Depth'}] = $DP;

				}

				# add Allelic balance (AB) of the Case in supplementary column
				if (defined $addCaseAB && $dicoSamples{$finalcol}{'columnName'} eq "Genotype-".$case){
					$finalSortData[$dicoColumnNbr{'Case AB'}] = $AB;

				}

				$finalSortData[$dicoColumnNbr{$dicoSamples{$finalcol}{'columnName'}}] = $genotype[$formatIndex{'GT'}];
				#concatenate sample genotype to build family genotype
				$familyGenotype .= $genotype[$formatIndex{'GT'}]."_";


		} #END of Sample Treatment


###################################################################################
######################### GENOTYPE ANALYSIS #######################################
###################################################################################
########## additionnal analysis in TRIO or affected context according to family genotype + CNV


		#Do next if index case is 0/0 in duo context
  		if (defined $duo){
			if ( $line[0]!~/X/){

    				if (defined $skipCaseWT && $finalSortData[$dicoColumnNbr{"Genotype-".$case}] eq "0/0"){
       					next;
	   			}
			}
		}

		#Penalize (or do next) if index case is 0/0 or parents are 1/1 and not affected. We should treat further all affected genotypes like this (!= 0/0)
		if (defined $trio){
			if ($line[0]!~/X/){

			if (defined $skipCaseWT && $finalSortData[$dicoColumnNbr{"Genotype-".$case}] eq "0/0"){
				switch ($familyGenotype){
					#Check if case/dad and case/mum  inheritance are  consistent
					case /^_0\/0_0\/1_0\/0_/ {$dadVariant ++ ;}
					case /^_0\/0_0\/0_0\/1_/ {$mumVariant ++ ;}
				}
    				next;
			}

			switch ($familyGenotype){
				#Check if case/dad and case/mum  inheritance are  consistent
				case /^_0\/0_0\/1_0\/0_/ {$dadVariant ++ ;}
				case /^_0\/0_0\/0_0\/1_/ {$mumVariant ++ ;}
				case /^_0\/1_0\/1_0\/0_/ {$caseDadVariant ++;}
				case /^_0\/1_0\/0_0\/1_/ {$caseMumVariant ++;}

			}
			}

			if ($finalSortData[$dicoColumnNbr{"Genotype-".$case}] eq "0/0" or (! defined $hashAffected{$dad} and $finalSortData[$dicoColumnNbr{"Genotype-".$dad}] eq "1/1") or (! defined $hashAffected{$mum} and $finalSortData[$dicoColumnNbr{"Genotype-".$mum}] eq "1/1") ){
				$finalSortData[$dicoColumnNbr{'MPA_ranking'}]   += 100;
			}
		}elsif (@affectedArray){
			foreach my $AFF (@affectedArray){
				if ($finalSortData[$dicoColumnNbr{"Genotype-".$AFF}] eq "0/0"){
					$finalSortData[$dicoColumnNbr{'MPA_ranking'}]   += 100;
					last;
				}
			}
			if ( scalar  @nonAffectedArray > 0){
				if ($finalSortData[$dicoColumnNbr{'MPA_ranking'}]   < 10){;
					foreach my $NAFF (@nonAffectedArray){
						if ($finalSortData[$dicoColumnNbr{"Genotype-".$NAFF}] eq "1/1"){
							$finalSortData[$dicoColumnNbr{'MPA_ranking'}]   += 100;
							last;
						}
					}
				}
			}
		}
		# TODO, add elsif with a foreach loop with affected that shouldn't be 0/0 and non-affected 1/1

		#

		if (defined $trio){

			switch ($familyGenotype){		#INFO you must use this switch syntax: case m/myRegex/ with complex regex (instead of case /regex/

				#find Autosomique Recessive
				#case ["_1/1_0/1_0/1_"] {$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#AUTOREC";}
				#TODO
				case m/^_1\/1_0\/1_0\/1_(1\/1_){$NTaffectedCmpt}(0\/1_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " AUTOREC"; $tagsHash{'AUTOREC'}{'count'} ++;   }


				#Find de novo
				#case ["_1/1_0/0_0/0_" ,"_0/1_0/0_0/0_"] {$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#DENOVO";

				#TODO
				case m/^_[01]\/1_0\/0_0\/0_([01]\/1_){$NTaffectedCmpt}(0\/0_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " DENOVO"; $tagsHash{'DENOVO'}{'count'} ++;

					foreach my $geneName (@geneList){
						unless(defined $dicoGeneForHTZcompo{$geneName}{'denovo'} ){$dicoGeneForHTZcompo{$geneName}{'denovo'} = 1 ;}
						$dicoGeneForHTZcompo{$geneName}{'variantID'} .= $variantID."#";
						$dicoGeneForHTZcompo{$geneName}{'MPA_ranking'} .= $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."#" ;
					}
				}




				#Find HTZ composite
				#case ["_0/1_0/1_0/0_"] {
				#TODO
				case m/^_0\/1_0\/1_0\/0_(0\/1_){$NTaffectedCmpt}(0\/[01]_){$NTnonAffectedCmpt}/ {

					foreach my $geneName (@geneList){
						unless(defined $dicoGeneForHTZcompo{$geneName}{'pvsm'} ){$dicoGeneForHTZcompo{$geneName}{'pvsm'} = 1 ;	}

						$dicoGeneForHTZcompo{$geneName}{'variantID'} .= $variantID."#";
						$dicoGeneForHTZcompo{$geneName}{'MPA_ranking'} .= $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."#" ;
					}
				}

				#case ["_0/1_0/0_0/1_"] {
				#TODO
				case m/^_0\/1_0\/0_0\/1_(0\/1_){$NTaffectedCmpt}(0\/[01]_){$NTnonAffectedCmpt}/ {

					foreach my $geneName (@geneList){
						unless(defined $dicoGeneForHTZcompo{$geneName}{'mvsp'} ){$dicoGeneForHTZcompo{$geneName}{'mvsp'} = 1 ;}

						$dicoGeneForHTZcompo{$geneName}{'variantID'} .= $variantID."#";
						$dicoGeneForHTZcompo{$geneName}{'MPA_ranking'} .= $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."#" ;
					}
				}

				#Find SNVvsCNV
				#case ["_1/1_0/0_0/1_"] {$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#SNPmCNVp";}
				#TODO
				case m/^_1\/1_0\/0_0\/1_(1\/1_){$NTaffectedCmpt}(0\/[01]_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " SNPmCNVp";$tagsHash{'SNPmCNVp'}{'count'} ++; }

				#case ["_1/1_0/1_0/0_"] {$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#SNPpCNVm";}
				#TODO
				case m/^_1\/1_0\/1_0\/0_(1\/1_){$NTaffectedCmpt}(0\/[01]_){$NTnonAffectedCmpt}/ {$worksheetTAG  .= " SNPpCNVm";$tagsHash{'SNPpCNVm'}{'count'} ++; }


				#case ["_0/1_0/1_0/1_"]	{
				#TODO
				case m/^_0\/1_0\/1_0\/1_(0\/1_){$NTaffectedCmpt}(0\/1_){$NTnonAffectedCmpt}/ {
					foreach my $geneName (@geneList){
						if(defined $dicoGeneForHTZcompo{$geneName}{'any'} ){
#							$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#SNPpCNVm";}
							# do nothing
						}else{
							$dicoGeneForHTZcompo{$geneName}{'any'} = 100 ;
						}
						$dicoGeneForHTZcompo{$geneName}{'variantID_any'} .= $variantID."#";
						$dicoGeneForHTZcompo{$geneName}{'MPA_ranking_any'} .= $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."#";
					}
				}

			}#END SWITCH

			#Check if CNV is present
			if (defined $finalSortData[$dicoColumnNbr{'SecondHit-CNV'}] && $finalSortData[$dicoColumnNbr{'SecondHit-CNV'}] ne "."){
				foreach my $geneName (@geneList){
					if(defined $dicoGeneForHTZcompo{$geneName}{'CNV'} ){
#						$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#SNPpCNVm";}
						# do nothing
					}else{
							$dicoGeneForHTZcompo{$geneName}{'CNV'} = 1 ;
					}

						$dicoGeneForHTZcompo{$geneName}{'variantID'} .= $variantID."#";
						$dicoGeneForHTZcompo{$geneName}{'MPA_ranking'} .= $finalSortData[$dicoColumnNbr{'MPA_ranking'}]."#" ;
				}

			}

		}elsif (scalar @affectedArray > 0){						#END IF TRIO

			# TODO open additionnal tab in non-trio contexte (affected and stangers)
			#Family Affected mode (non-trio)
			switch ($familyGenotype){

				#find Autosomique Recessive
				case m/^_(1\/1_){$NTaffectedCmpt}(0\/1_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " AUTOREC";$tagsHash{'AUTOREC'}{'count'} ++; }

				#Find de novo
				case m/^_(1\/1_){$NTaffectedCmpt}(0\/0_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " DENOVO";$tagsHash{'DENOVO'}{'count'} ++; }
				case m/^_(0\/1_){$NTaffectedCmpt}(0\/0_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " DENOVO";$tagsHash{'DENOVO'}{'count'} ++; }

				#Find HTZ composite or should be "dominant" term
				case m/^_(0\/1_){$NTaffectedCmpt}(0\/[01]_){$NTnonAffectedCmpt}/ {$worksheetTAG .= " SNPmCNVp";$tagsHash{'SNPmCNVp'}{'count'} ++; }

			}


		}else{  #END OF AFFECTED

			#Stranger Mode
			@strangerNULL = $familyGenotype =~ m/\.\/\./g;
			@strangerREF = $familyGenotype =~ m/0\/0/g;
			@strangerHTZ = $familyGenotype =~ m/0\/1/g;
			@strangerHMZ = $familyGenotype =~ m/1\/1/g;

			if (scalar @strangerHTZ > 0 && scalar @strangerHTZ < 2 && (scalar @strangerNULL + scalar @strangerREF + scalar @strangerHTZ == $cmpt)){
				$worksheetTAG .= " DENOVO";$tagsHash{'DENOVO'}{'count'} ++;
				#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#DENOVO";
			}elsif (scalar @strangerHMZ > 0 && scalar @strangerHMZ < 2 && (scalar @strangerNULL + scalar @strangerREF + scalar @strangerHTZ + scalar @strangerHMZ == $cmpt)){
				$worksheetTAG .= " AUTOREC";$tagsHash{'AUTOREC'}{'count'} ++;
			}elsif (scalar @strangerHMZ > 0 && scalar @strangerHMZ < 2 && (scalar @strangerNULL + scalar @strangerREF + scalar @strangerHMZ == $cmpt)){
				$worksheetTAG .= " SNPmCNVp";$tagsHash{'SNPmCNVp'}{'count'} ++;
			}

		}  # END OF STRANGER MODE





		#	print Dumper(\@finalSortData);

#############################################################################
######### FILL HASH STRUCTURE WITH COMMENTS


		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'finalArray'} = [@finalSortData] ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'nbSample'} = scalar keys %dicoSamples ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentGnomADexome'} = $commentGnomADExomeScore  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentGnomADgenome'} = $commentGnomADGenomeScore ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentGenotype'} = $commentGenotype ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentMPAscore'} = $commentMPAscore  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentInterVar'} = $commentInterVar  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentFunc'} = $commentFunc  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentPhenotype'} = $commentPhenotype  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentClinvar'} = $commentClinvar  ;
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'genotypeMozaic'} = $mozaicSamples ;
		
		#deal with URL
		if ($mdAPIkey ne ""){
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'MDurl'} = $mdAPIkey.$finalSortData[$dicoColumnNbr{'#CHROMPOSREFALT'}];
		}else{
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'MDurl'} = "https://mobidetails.iurc.montp.inserm.fr/MD/vars/".$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}];
		}	
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'Franklinurl'} = $franklinURL.$finalSortData[$dicoColumnNbr{'#CHROMPOSREFALT'}]."-".$build;
		

		# attribute mozaic color
		foreach my $colNbr (keys %hashColor){
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'hashColor'}{$colNbr} = $hashColor{$colNbr} ;
		}


		#initialize worksheet
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} = $worksheetTAG;
		#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} = "";

		#test multiple geneNames
		#@geneList = split(';', $finalSortData[$dicoColumnNbr{'Gene.'.$refGene}] );

		foreach my $geneName (@geneList){

			#ACMG
			#if(defined $ACMGgene{$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}]} )
			if(defined $ACMGgene{$geneName} ){

				if (defined $hideACMG){
					$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} = "ACMG warning\n\n";	
                    $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  '#FFFFFF' ;
				}else{
					$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= " ACMG";
					$tagsHash{'ACMG'}{'count'} ++;
				}
			}

			#CANDIDATES
			if($candidates ne ""){
				#if(defined $candidateGene{$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}]} )
				if(defined $candidateGene{$geneName} ){
					#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .= "#CANDIDATES";
					$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'worksheet'} .=    " ".$candidateGene{$geneName};
					#print 	" ".$candidateGene{$geneName}."\n";

					my @pathoTAG = split( ' ', $candidateGene{$geneName} );
					for(my $i=0; $i < scalar @pathoTAG; $i ++){
						$tagsHash{$pathoTAG[$i]}{'count'} ++;
						#print $pathoTAG[$i]."__________\n";
					}
				}

			}

			#PHENOLYZER COMMENT AND SCORE

			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentPhenolyzer'} = "";

			#if(defined  $phenolyzerGene{$finalSortData[$dicoColumnNbr{'Gene.'.$refGene}]})
			if(defined  $phenolyzerGene{$geneName}){
				$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentPhenolyzer'} .= $phenolyzerGene{$geneName}{'comment'}."\n\n"  ;

			}

		}#END FOREACH




###############################################################
		# TODO switch to LOEUF system
##########create pLI comment and format
		#if(defined $dicoInfo{'pLi.'.$refGene} && $dicoInfo{'pLi.'.$refGene} ne "." ){
		if(defined $dicoInfo{'oe_lof_upper_bin.'.$refGene} && $dicoInfo{'oe_lof_upper_bin.'.$refGene} ne "." ){

			#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} =  "pLI = ".$dicoInfo{'pLi.'.$refGene}."\npRec = ".$dicoInfo{'pRec.'.$refGene}."\npNull = ".$dicoInfo{'pNull.'.$refGene} ."\n\n";

#            oe_lof_upper_rank   oe_lof_upper_bin    oe_lof  oe_lof_lower    oe_lof_upper    oe_mis  oe_mis_lower    oe_mis_upper

			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .=  "LOEUF = ".$dicoInfo{'oe_lof_upper.'.$refGene}."\nLOEUF_decile = ".$dicoInfo{'oe_lof_upper_bin.'.$refGene}."\n\noe_lof = ".$dicoInfo{'oe_lof.'.$refGene}."\noe_lof_lower = ".$dicoInfo{'oe_lof_lower.'.$refGene} ."\n\n";

            if( $dicoInfo{'oe_lof_upper_bin.'.$refGene} =~ /;/){

                my @tweenBin = split( ';', $dicoInfo{'oe_lof_upper_bin.'.$refGene}   );

                if ($tweenBin[1] eq "." && $tweenBin[0] ne "."){
			        $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  $dicoLOEUFformatColor{$tweenBin[0]} ;
                }elsif($tweenBin[0] eq "." && $tweenBin[1] ne "."){

			        $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  $dicoLOEUFformatColor{$tweenBin[1]} ;
                }elsif($tweenBin[0] eq "." && $tweenBin[1] eq "."){
                    $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  '#FFFFFF' ;

                }elsif($tweenBin[0] >= $tweenBin[1]){
                     $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  $dicoLOEUFformatColor{$tweenBin[1]} ;
                }else{
                     $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  $dicoLOEUFformatColor{$tweenBin[0]} ;
                }

            }else{

			#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  sprintf('#%2.2X%2.2X%2.2X',($dicoInfo{'pLi.'.$refGene}*255 + $dicoInfo{'pRec.'.$refGene}*255),($dicoInfo{'pRec.'.$refGene}*255 + $dicoInfo{'pNull.'.$refGene} * 255),0) ;

			    $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  $dicoLOEUFformatColor{$dicoInfo{'oe_lof_upper_bin.'.$refGene}} ;

            }

            #add color format
			$format_pLI = $workbook->add_format(bg_color => $hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'});



			if(defined $dicoInfo{'oe_mis_upper.'.$refGene} && $dicoInfo{'oe_mis_upper.'.$refGene} ne "." ){
			#if(defined $dicoInfo{'Missense_Z_score.'.$refGene} && $dicoInfo{'Missense_Z_score.'.$refGene} ne "." ){
				#$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .=  "Missense Z-score = ".$dicoInfo{'Missense_Z_score.'.$refGene}."\n\n";
				$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .=  "Missense_upper = ".$dicoInfo{'oe_mis_upper.'.$refGene}."\n\n";
			}

		}else{

			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .=  "." ;
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'colorpLI'} =  '#FFFFFF' ;

			#$format_pLI = $workbook->add_format(bg_color => '#FFFFFF');
		}

###############################################################
##########Add function and expression infos in comment
		if(defined $dicoInfo{'Function_description.'.$refGene}  && $dicoInfo{'Function_description.'.$refGene} ne "." ){
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .= "Function Description:\n".$dicoInfo{'Function_description.'.$refGene}."\n\n";

			if(defined $dicoInfo{'Tissue_specificity(Uniprot).'.$refGene} && $dicoInfo{'Tissue_specificity(Uniprot).'.$refGene} ne "."  ){
			$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'commentpLI'} .= "Tissue specificity:\n".$dicoInfo{'Tissue_specificity(Uniprot).'.$refGene}."\n";
			}

		}


	} #END of IF-ELSE(#CHROM)





#DEBUG			print Dumper(\%dicoColumnNbr);
##############check hereditary hypothesis or genes to fill sheets





############ THE TIME HAS COME TO FILL THE XLSX OUTPUT FILE





}#END WHILE VCF


########################################################################
###################	Compute HTZ compo before writing

foreach my $geneName (sort keys %dicoGeneForHTZcompo){


	#my $MPA = $dicoGeneForHTZcompo{$geneName}{'HTZscore'};
	#my $variant = $dicoGeneForHTZcompo{$geneName}{'HTZscore'};

	if(defined 	$dicoGeneForHTZcompo{$geneName}{'CNV'}){
		$dicoGeneForHTZcompo{$geneName}{'HTZscore'} += 1  ;
	}
	if(defined 	$dicoGeneForHTZcompo{$geneName}{'denovo'}){
		$dicoGeneForHTZcompo{$geneName}{'HTZscore'} += 1  ;
	}
	if(defined 	$dicoGeneForHTZcompo{$geneName}{'HTZscore'} && $dicoGeneForHTZcompo{$geneName}{'HTZscore'} > 0 && defined $dicoGeneForHTZcompo{$geneName}{'any'} ){
		$dicoGeneForHTZcompo{$geneName}{'HTZscore'} += 100;
	}
	if(defined 	$dicoGeneForHTZcompo{$geneName}{'pvsm'}){
		$dicoGeneForHTZcompo{$geneName}{'HTZscore'} += 1 ;
	}
	if(defined 	$dicoGeneForHTZcompo{$geneName}{'mvsp'}){
		$dicoGeneForHTZcompo{$geneName}{'HTZscore'} += 1  ;
	}

	if(defined $dicoGeneForHTZcompo{$geneName}{'HTZscore'}  && $dicoGeneForHTZcompo{$geneName}{'HTZscore'} > 1  ){
		#DEBUG
		#print $geneName."\t".$dicoGeneForHTZcompo{$geneName}{'HTZscore'}."\n";


		my @variantList = split( '#', $dicoGeneForHTZcompo{$geneName}{'variantID'} );
		my @MPAList = split( '#', $dicoGeneForHTZcompo{$geneName}{'MPA_ranking'} );

		for(my $i=0; $i < scalar @variantList; $i ++){

			unless(defined	$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheetHTZcompo'}){
				$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheetHTZcompo'} = "#HTZcompo";
				$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheet'} .= " HTZcompo";
				$tagsHash{'HTZcompo'}{'count'} ++;


				#create reference of Hashes
				my $hashTemp = $hashFinalSortData{$MPAList[$i]}{$variantList[$i]};
				my $hashColumn_ref = \%dicoColumnNbr;

##############################################################
###########################      HTZ composite     #####################

				#Write the HTZcompo worksheet
				writeThisSheet ($worksheetHTZcompo,
								$worksheetLineHTZcompo,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
								);
				$worksheetLineHTZcompo ++;

			}#END unless

		}#END FOR



	}#END HTZscore >1

	if( defined $dicoGeneForHTZcompo{$geneName}{'HTZscore'} && $dicoGeneForHTZcompo{$geneName}{'HTZscore'} > 100  ){
		#DEBUG
		#print $geneName."\t".$dicoGeneForHTZcompo{$geneName}{'HTZscore'}."\n";


		my @variantList = split( '#', $dicoGeneForHTZcompo{$geneName}{'variantID_any'} );
		my @MPAList = split( '#', $dicoGeneForHTZcompo{$geneName}{'MPA_ranking_any'} );

		for(my $i=0; $i < scalar @variantList; $i ++){

			unless(defined	$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheetHTZcompo'}){
				$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheetHTZcompo'} = "#HTZcompo";
				$hashFinalSortData{$MPAList[$i]}{$variantList[$i]}{'worksheet'} .= " HTZcompo";
				$tagsHash{'HTZcompo'}{'count'} ++;


				#create reference of Hashes
				my $hashTemp = $hashFinalSortData{$MPAList[$i]}{$variantList[$i]};
				my $hashColumn_ref = \%dicoColumnNbr;

##############################################################
###########################      HTZ composite     #####################

				#Write the HTZcompo worksheet
				writeThisSheet ($worksheetHTZcompo,
								$worksheetLineHTZcompo,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
								);
				$worksheetLineHTZcompo ++;

			}#END unless

		}#END FOR

	}#END HTZscore >100

}

####################################################################
######################## HTML  Initialisation ######################

#file header




my $htmlStart = "<!DOCTYPE html>\n<html>
\n<head>
\n<meta charset=\"utf-8\">
\n<title>".$outPrefix." Achab catch</title>\n
\n<script type=\"text/javascript\" language=\"javascript\" src='https://code.jquery.com/jquery-3.5.1.js'></script>
\n<script type=\"text/javascript\" language=\"javascript\" src='https://cdn.datatables.net/1.10.22/js/jquery.dataTables.min.js'></script>
\n<script type=\"text/javascript\" language=\"javascript\" src='https://cdn.datatables.net/fixedheader/3.1.7/js/dataTables.fixedHeader.min.js'></script>
\n<script>

var filter;

\$(document).ready(function () {


	\$('#table thead tr').clone(true).appendTo( '#table thead' );
            \$('#table thead tr:eq(1) th').each( function (i) {
             var title = \$(this).text();
				\$(this).html( '<input type=\"text\" placeholder=\"Search\" />' );
				\$(this).removeClass('rotate').off('click');
              \$( 'input', this ).on( 'keyup change', function () {
                  if ( table.column(i).search() !== this.value ) {
                        table
                       .column(i)
                       .search( this.value )
                       .draw();
                  }
            } );
        } );




	var table = \$('#table').DataTable(        {\"dom\": 'ift', \"order\": [] ,\"lengthMenu\":[ [ -1 ],[ \"All\" ]], \"fixedHeader\": true, \"orderCellsTop\": true, \"oLanguage\": {\"sInfo\": \"TOTAL: _TOTAL_ lines\" } } );


filter = function  (evt, cat) {

	var metadata = document.getElementsByClassName(\"META\");

	if (cat === \"META\"){

		document.getElementById(\"ALL\").style.visibility = \"collapse\";

		for (i = 0; i < metadata.length; i++) {
			metadata[i].style.display = \"block\";
		}

	}else{

		for (i = 0; i < metadata.length; i++) {
			metadata[i].style.display = \"none\";
		}

		document.getElementById(\"ALL\").style.visibility = \"visible\";

		var rowunselected = document.getElementsByTagName(\"TR\");
		for (i = 0; i < rowunselected.length; i++) {
			rowunselected[i].style.visibility = \"collapse\";
		}
		var rowselect = document.getElementById('table').getElementsByClassName(cat);
		for (i = 0; i < rowselect.length; i++) {
			rowselect[i].style.visibility = \"visible\";
		}

		var rowhead = document.getElementById('table').getElementsByClassName('head');
		for (i = 0; i < rowhead.length; i++) {
			rowhead[i].style.visibility = \"visible\";
		}

		var tablinks = document.getElementsByClassName(\"tablinks\");
		for (i = 0; i < tablinks.length; i++) {
			tablinks[i].className = tablinks[i].className.replace(\" active\", \"\");
		}


	}

	evt.currentTarget.className += \" active\";

	window.scrollTo(0, 0);

}

/*double click on favorite row*/
	\$('#table tbody').on('dblclick', 'tr', function () {
		this.classList.toggle('favorite');
	} );


});


</script>
\n<link rel=\"stylesheet\" type=\"text/css\" href='https://cdn.datatables.net/1.10.22/css/jquery.dataTables.min.css'>
\n<link rel=\"stylesheet\" type=\"text/css\" href='https://cdn.datatables.net/fixedheader/3.1.7/css/fixedHeader.dataTables.min.css'>

\n<style>



/* Style the tab */
        .tab {
                overflow: hidden;
                border: 1px solid #ccc;
                background-color: #f1f1f1;
                left: 0;
                bottom: 0;
                position: fixed;
                position: -webkit-sticky;
                position: sticky;
                }

/* Style the buttons inside the tab */
        .tab input {
                background-color: inherit;
                float: left;
                border: none;
                outline: none;
                cursor: pointer;
                padding: 14px 16px;
                transition: 0.3s;
                font-size: 17px;
                }
/* Change background color of buttons on hover */
        .tab input:hover {
                background-color: #ddd;
                }



/* Create an active/current tablink class */
        .tab input.active {
                background-color: #ccc;
                }
/*        .tab input:focus {
                background-color: #ccc;
                }*/
		#ALL tbody tr.favorite{
			background-color: goldenrod;
		}
		#ALL tbody tr:hover{
			background-color: teal;
		}
		#ALL tbody tr td div{
			max-height: 45px;
			text-overflow : ellipsis;
			-o-text-overflow: ellipsis;
			-ms-text-overflow: ellipsis;
			-moz-binding: url('ellipsis.xml#ellipsis');
			overflow: hidden;
			white-space: nowrap;
		}
		#ALL tbody tr td div:hover{
			overflow: visible;
			white-space : pre-line;
			overflow-wrap : break-word;
		}
		td {
			text-align: center;
		}

/*rotate header*/
        thead input {
                width: 100%;
                }
		th.rotate {
			height: 150px;
			white-space: nowrap;
		}
		th.rotate > div {
			transform:
				translate(25px, 51px)
				rotate(315deg);
				width: 30px;
		}
		th.rotate > div > span {
			/*border-bottom: 1px solid #ccc;*/
			padding: 5px 10px;
		}



/* Style METADATA */
		.META {
			display: none;
			white-space: pre-line;
		}

/* Style the tab content */
        .tabcontent {
                visibility: visible;
                padding: 6px 12px;
                /*border: 1px solid #ccc;*/
                border-top: none;
                }

/* Style the tooltip div */

        .tooltip {
                position: relative;
                display: inline-block;
                /*border-bottom: 1px dotted black;*/
                max-width: 120px;
                word-wrap: break-word;
                }

        .tooltip .tooltiptext {
                visibility: hidden;
                width: auto;
                min-width: 300px;
                max-width: 600px;
                height: auto;
                background-color: #555;
                color: #fff;
                text-align: left;
                border-radius: 6px;
                padding: 5px 0;
                position: absolute;
                z-index: 1;
                top: 100%;
                left: 20%;
                margin-left: -20px;
                opacity: 0;
                transition: opacity 0.3s;
                overflow: hidden;
                text-overflow: ellipsis;
                white-space: pre-line;
                overflow-wrap: break-word;
                }

        .tooltip:hover .tooltiptext {
                visibility: visible;
                opacity: 1;
                }



\n</style>



\n</head>
\n\t<body>";


#METADATA
$vcfHeader =~ s/[<>]//g;
my $metadata = "<div class=\"META\"><b>Arguments:</b><br>".$achabArg."<br><br><br><b>VCF Header:</b><br>".$vcfHeader."</div>\n";


#table and columns names


my $htmlStartTable = "";
foreach my $col (@columnTitles){
	#print HTML "\t<th style=\"word-wrap: break-word\"   >";
	$htmlStartTable .= "\t<th class=\"rotate\" ><div><span>".$col."\t</span></div></th>\n";
}
$htmlStartTable .= "</tr>\n</thead>\n<tbody>\n";



my $htmlALL= $metadata."<div id=\"ALL\" class=\"tabcontent\">\n\t<table id='table' class=\"display compact\" >\n\t\t<thead><tr class=\"head\">".$htmlStartTable;

#my $htmlMETA="<div id=\"METADATA\" class=\"tabcontent\">\n\t<table id='tabMETADATA' class='display' >\n\t\t<thead><tr>".$htmlStartTable;


my $htmlEndTable = "</tbody>\n</table>\n</div>\n\n\n";

my $htmlEnd = "<div class=\"tab\">\n<input type=\"button\" class=\"tablinks\" value=\"ALL_".$popFreqThr."\" onclick=\"filter(event, 'ALL')\">\n<input type=\"button\" class=\"tablinks\" value=\"*Favorites*\" onclick=\"filter(event, 'favorite')\">\n" ;

#sort tag by number of variant

my @tagSort = sort { $tagsHash{$b}{'count'}<=>  $tagsHash{$a}{'count'}  } keys %tagsHash ;
foreach my $tag ( @tagSort){
		#print $tag."_".$tagsHash{$tag}{'label'}."\n";
		$htmlEnd .= "<input type=\"button\" class=\"tablinks\" value=\"".$tagsHash{$tag}{'label'}." (".$tagsHash{$tag}{'count'}.")\" onclick=\"filter(event, '".$tag."')\" >\n" ;
}
#foreach my $tag ( keys %tagsHash){
#		print $tag."_".$tagsHash{$tag}{'label'}."\n";
#		$htmlEnd .= "<input type=\"button\" class=\"tablinks\" value=\"".$tagsHash{$tag}{'label'}." (".$tagsHash{$tag}{'count'}.")\" onclick=\"filter('".$tag."')\" >\n" ;
#}
$htmlEnd .= "</div>" ;

$htmlEnd .= "\n</body>\n</html>";

my $newHopePrefix = "";
if(defined $newHope){
	$newHopePrefix = "newHope_";
}


open(HTML, '>', $outDir."/".$outPrefix.$newHopePrefix."achab.html") or die $!;


#########################################################################
#################### Sort by MPA ranking for the output

#create user friendly ranking score
my $kindRank=0;


foreach my $rank (sort {$a <=> $b} keys %hashFinalSortData){
	#print $rank."\n";

	foreach my $variant ( keys %{$hashFinalSortData{$rank}}){

#		$format_pLI = $workbook->add_format(bg_color => '#FFFFFF');

		#increse rank number then change final array
		$kindRank++;

		#print $variant ."___".  $hashFinalSortData{$rank}{$variant}{'finalArray'}[$dicoColumnNbr{'MPA_ranking'}]."\n";
		$hashFinalSortData{$rank}{$variant}{'finalArray'}[$dicoColumnNbr{'MPA_ranking'}] = $kindRank;

		#last finalSortData assignation
		$hashFinalSortData{$finalSortData[$dicoColumnNbr{'MPA_ranking'}]}{$variantID}{'finalArray'} = [@finalSortData] ;

		#print Dumper($hashFinalSortData{$rank}{$variant}{'finalArray'});

		#create reference of Hashes
		my $hashTemp = $hashFinalSortData{$rank}{$variant};
		my $hashColumn_ref = \%dicoColumnNbr;



#FILL tab 'ALL';
$htmlALL .= "<tr class=\"ALL".$hashFinalSortData{$rank}{$variant}{'worksheet'}."\" >\n";



for( my $fieldNbr = 0 ; $fieldNbr < scalar @{$hashFinalSortData{$rank}{$variant}{'finalArray'}} ; $fieldNbr++){

#foreach my $field ( @{$hashFinalSortData{$rank}{$variant}{'finalArray'}} ){
	#print HTML "\t<td style=\"word-wrap: break-word\";class=\"tooltip\"; title=".$field."  >";
	#print HTML "\t<td >";


	switch ($fieldNbr){
		case ( 0 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentMPAscore'}."</span></div>"   }
		case ( 1 ) { $htmlALL .= "\t<td ><div class=\"tooltip\"><a href=\"".$hashFinalSortData{$rank}{$variant}{'MDurl'}."\"target=\"_blank\" rel=\"noopener noreferrer\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."</a><span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentFunc'}."</span></div> "   }
		case ( 2 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentPhenolyzer'}."</span></div> "   }
		case ( 3 ) { $htmlALL .= "\t<td style=\"background-color:".$hashFinalSortData{$rank}{$variant}{'colorpLI'}."\"><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentpLI'}."</span></div>    "   }
		case ( 4 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."\n".$hashFinalSortData{$rank}{$variant}{'commentPhenotype'}."</span></div> "   }
		case ( 5 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentGnomADgenome'}."</span></div> "   }
		case ( 6 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentGnomADexome'}."</span></div> "   }
		case ( 7 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentClinvar'}."</span></div> "   }
		case ( 8 ) { $htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentInterVar'}."</span></div> "   }
		case ( 10 ) {
			if ( defined $hashFinalSortData{$rank}{$variant}{'hashColor'}{$fieldNbr}){
				$htmlALL .= "\t<td style=\"background-color:".$hashFinalSortData{$rank}{$variant}{'hashColor'}{$fieldNbr}."\"><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentGenotype'}."</span></div>";
			}else{
				$htmlALL .= "\t<td ><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."<span class=\"tooltiptext tooltip-bottom\">".$hashFinalSortData{$rank}{$variant}{'commentGenotype'}."</span></div>";
			}
		}
		case ( $dicoColumnNbr{'#CHROMPOSREFALT'} ) { $htmlALL .= "\t<td ><div class=\"tooltip\"><a href=\"".$hashFinalSortData{$rank}{$variant}{'Franklinurl'}."\"target=\"_blank\" rel=\"noopener noreferrer\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."</a></div> "  ;
		}	
		else{
			if ( defined $hashFinalSortData{$rank}{$variant}{'hashColor'}{$fieldNbr}){
				$htmlALL .= "\t<td style=\"background-color:".$hashFinalSortData{$rank}{$variant}{'hashColor'}{$fieldNbr}."\"><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."</div>";
			}else{
				if (defined $hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]){
					$htmlALL .= "\t<td><div class=\"tooltip\">".$hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]."</div>" ;
				}else{
					$htmlALL .= "\t<td><div class=\"tooltip\">.</div>" ;
				}
			}
		}
	}




	#if (defined $hashFinalSortData{$rank}{$variant}{'finalArray'}[$fieldNbr]){
	#}else {
#		$htmlALL .= "."
#	}
	$htmlALL .= "\t</td>\n";

}

#print HTML "</tr>\n";
$htmlALL .= "</tr>\n";





##############################################################
###########################      ALL     #####################

		writeThisSheet ($worksheet,
						$worksheetLine,
						$format_pLI,
						$case,
						$hashTemp,
						$hashColumn_ref	);
		$worksheetLine ++;

#						$hashFinalSortData{$rank}{$variant}{'commentMPAscore'},
#						$hashFinalSortData{$rank}{$variant}{'commentGnomADgenome'},
#						$hashFinalSortData{$rank}{$variant}{'commentGnomADgenome'},
#						$hashFinalSortData{$rank}{$variant}{'commentGenotype'},
#						$hashFinalSortData{$rank}{$variant}{'commentFunc'},
#						$hashFinalSortData{$rank}{$variant}{'commentPhenotype'},
#						$hashFinalSortData{$rank}{$variant}{'commentPhenolyzer'},
#						$hashFinalSortData{$rank}{$variant}{'commentInterVar'},
#						$hashFinalSortData{$rank}{$variant}{'commentpLI'},
#						$hashFinalSortData{$rank}{$variant}{'colorpLI'},
#						$hashFinalSortData{$rank}{$variant}{'finalArray'},
#						%dicoColumnNbr






##############################################################
################# ACMG DS #############

		if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /ACMG/){

			writeThisSheet ($worksheetACMG,
							$worksheetLineACMG,
							$format_pLI,
							$case,
							$hashTemp,
							$hashColumn_ref
						);

			$worksheetLineACMG ++;
		}



##############################################################
################# OMIM DOMINANT #############

		if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /OMIMDOM/){

			writeThisSheet ($worksheetOMIMDOM,
							$worksheetLineOMIMDOM,
							$format_pLI,
							$case,
							$hashTemp,
							$hashColumn_ref
						);

			$worksheetLineOMIMDOM ++;
		}



##############################################################
################# OMIM RECESSIVE #############

		if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /OMIMREC/){

			writeThisSheet ($worksheetOMIMREC,
							$worksheetLineOMIMREC,
							$format_pLI,
							$case,
							$hashTemp,
							$hashColumn_ref
						);

			$worksheetLineOMIMREC ++;
		}




##############################################################
################ CANDIDATES #############



	foreach my $patho (keys %candidWorksheetHash){

		if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ / CANDID_$patho| CANDIDATES/    ){
			#	if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /CANDID/){

			writeThisSheet ($candidWorksheetHash{$patho}{'workbook'},
							$candidWorksheetHash{$patho}{'line'},
							$format_pLI,
							$case,
							$hashTemp,
							$hashColumn_ref
						);



			$candidWorksheetHash{$patho}{'line'} ++;
		}
	}



##############################################################
#################### GENOTYPE SELECTION ################
##############################################################


##############################################################
################ DENOVO  ######################
			if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /DENOVO/){

				writeThisSheet ($worksheetDENOVO,
								$worksheetLineDENOVO,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
							);
				$worksheetLineDENOVO ++;

				next;

			}


##############################################################
################  AUTOSOMIC RECESSIVE HOMOZYGOUS ###############
			if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /AUTOREC/){

				writeThisSheet ($worksheetAR,
								$worksheetLineAR,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
							);
				$worksheetLineAR ++;

				next;

			}

##############################################################
################ SNPvsCNV ##########################


			if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /SNPmCNVp/){

				writeThisSheet ($worksheetSNPmumVsCNVdad,
								$worksheetLineSNPmumVsCNVdad,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
							);
				$worksheetLineSNPmumVsCNVdad ++;

				next;

			}

		if(defined $trio){

			if( $hashFinalSortData{$rank}{$variant}{'worksheet'} =~ /SNPpCNVm/) {

				writeThisSheet ($worksheetSNPdadVsCNVmum,
								$worksheetLineSNPdadVsCNVmum,
								$format_pLI,
								$case,
								$hashTemp,
								$hashColumn_ref
							);

				$worksheetLineSNPdadVsCNVmum ++;
				next;

			}

		}   # END IF TRIO

	}   # END FOREACH VARIANT
}	#END FOREACH RANK






#############add autofilters within the sheets

$worksheet->autofilter('A1:AZ'.$worksheetLine); # Add autofilter until the end
$worksheetOMIMDOM->autofilter('A1:AZ'.$worksheetLineOMIMDOM); # Add autofilter until the end
$worksheetOMIMREC->autofilter('A1:AZ'.$worksheetLineOMIMREC); # Add autofilter until the end


my $metadataLine = 1;

my $dadRatio = 0;
my $dadPoolRatio = 0;
my $mumRatio = 0;
my $mumPoolRatio = 0;

if(defined $trio){

	$worksheetHTZcompo->autofilter('A1:AZ'.$worksheetLineHTZcompo); # Add autofilter
	$worksheetSNPdadVsCNVmum->autofilter('A1:AZ'.$worksheetLineSNPdadVsCNVmum); # Add autofilter



	#check inheritance consistency and add to METADATA : log(transmis/nontransmis) between -0.13 and 0.1
 	if ( $dadVariant > 0 && $mumVariant > 0 && $caseDadVariant > 0 && $caseMumVariant > 0){
       
		#approximative correction of pooled dad and mum number variant by 4 (pool of 4)  
		$dadRatio = log($caseDadVariant/$dadVariant) / log(10); 
		$dadPoolRatio = log($caseDadVariant/($dadVariant/4)) / log(10);
		
		$mumRatio = log($caseMumVariant/$mumVariant) / log(10); 
		$mumPoolRatio = log($caseMumVariant/($mumVariant/4)) / log(10);
	
		if (  -0.13 < $dadRatio && $dadRatio <= 0.1  ){
			$worksheetMETA->write($metadataLine , 0, "Dad status : OK ".$dadRatio." [log10(".$caseDadVariant."/".$dadVariant."] is in the range -0.13 to 0.1), log10 of Inherited Heterozygous variants Ratio tends toward 0." );
		}else{
			$worksheetMETA->write($metadataLine , 0, "Dad status : BAD [log10(".$caseDadVariant."/".$dadVariant."] is out of range -0.13 to 0.1), log10 of Inherited Heterozygous variants Ratio tends toward 0." );
		}
		$metadataLine ++;
		
		if (  -0.13 <= $dadPoolRatio && $dadPoolRatio <= 0.1  ){
			$worksheetMETA->write($metadataLine , 0, "Dad Pool status : OK ".$dadPoolRatio." (log10(".$caseDadVariant."/(".$dadVariant."/4)) is in the range -0.13 to 0.1), log10 of Inherited Heterozygous variants Ratio tends toward 0." );
		}else{
			$worksheetMETA->write($metadataLine , 0, "Dad Pool status : BAD ". $dadPoolRatio." (log10(".$caseDadVariant."/(".$dadVariant."/4)) is out of range -0.13 to 0.1), log10 of Inherited Heterozygous variants Ratio tends toward 0." );
		}

		$metadataLine ++;

		if ( log($caseMumVariant/$mumVariant) / log(10) < 0.1  && log($caseMumVariant/$mumVariant) / log(10) > -0.13 ){
			$worksheetMETA->write($metadataLine , 0, "Mum status : OK (log10(".$caseMumVariant."/".$mumVariant.") is in the range -0.13 to 0.1), Inherited Heterozygous variants Ratio tends toward 0." );
		}else{
			$worksheetMETA->write($metadataLine , 0, "Mum status : BAD (log10(".$caseMumVariant."/".$mumVariant.") is out of range -0.13 to 0.1), Inherited Heterozygous variants Ratio tends toward 0." );
		}

		$metadataLine ++;
	}

}


#write arguments
$worksheetMETA->write($metadataLine , 0, "Arguments:" );
$metadataLine ++;
$worksheetMETA->write($metadataLine , 0, $achabArg );
$metadataLine ++;

# write IDSNP
if (defined $dicoColumnNbr{'ID'}){
	$worksheetMETA->write( $metadataLine, 0, $hashIDSNP{$finalSortData[$dicoColumnNbr{'ID'}]} );
	$metadataLine ++;
}

#write top 100 genes scored by phenolyzer
if (%phenolyzerGene){
	$worksheetMETA->write( $metadataLine, 0, "TOP 50 Genes scored by phenolyzer:" );
	$metadataLine ++;

	my @phenoSort = sort { $phenolyzerGene{$a}{'rank'}<=>  $phenolyzerGene{$b}{'rank'}  } keys %phenolyzerGene ;
	for ( my $i=0; $i <= 50; $i++){
		if ($i == scalar @phenoSort){
			last;
		}
		$worksheetMETA->write( $metadataLine, 0, $phenoSort[$i]);
		$worksheetMETA->write( $metadataLine, 1, $phenolyzerGene{$phenoSort[$i]}{'Raw'});
		$metadataLine ++;
	}
	$metadataLine ++;
}

#write vcf Header
$worksheetMETA->write( $metadataLine, 0, "VCF Header:" );
$metadataLine ++;
$worksheetMETA->write( $metadataLine , 0, $vcfHeader );
$metadataLine ++;

#intersect evaluation
$metadataLine ++;
$metadataLine ++;
$worksheetMETA->write( $metadataLine, 0, "Intersect VCF evaluation:" );
$metadataLine ++;

my $seenCounter = 0;
my $interVcfSize = 0;
if($intersectVCF_File ne ""){
	foreach my $var (keys %intersectVCF_variant){
		if (defined $intersectVCF_variant{$var}{"seen"}){
			$interVcfSize ++;
			if ($intersectVCF_variant{$var}{"seen"} > 0){
				$seenCounter ++;
			}
		}	
	}
	$worksheetMETA->write( $metadataLine, 0, "Nb variants to intersect (current/intersect): ".$count." / ".$interVcfSize );
	$metadataLine ++;
	$worksheetMETA->write( $metadataLine, 0, "Nb intersected variants: ".$seenCounter );
	$metadataLine ++;
}

# Add autofilter
$worksheetSNPmumVsCNVdad->autofilter('A1:AZ'.$worksheetLineSNPmumVsCNVdad); # Add autofilter
$worksheetAR->autofilter('A1:AZ'.$worksheetLineAR); # Add autofilter
$worksheetDENOVO->autofilter('A1:AZ'.$worksheetLineDENOVO); # Add autofilter


# fill Candidates
if($candidates ne ""){
	foreach my $patho (keys %candidWorksheetHash){
		my $toto = $candidWorksheetHash{$patho}{'workbook'};
		$candidWorksheetHash{$patho}{'workbook'}->autofilter('A1:AZ'.$candidWorksheetHash{$patho}{'line'});
	 }
 }

#hide ACMG tab
if (defined $hideACMG){
	$worksheetACMG->hide();
}

$workbook->close();
close(VCF);


print HTML $htmlStart;
#print HTML $htmlEndTable;
print HTML $htmlALL;
print HTML $htmlEndTable;
print HTML $htmlEnd;


close(HTML);

###############   ENd of VCF processing #####################
#
#



# Create a new Excel workbook for poor coverage
#
#



# Add all worksheets
my $workbookCoverage;
my $worksheetCoverage;
my $worksheetCoverageLine = 0;


#poor coverage and genemap2 treatment
if ($poorCoverage_File ne "" &&  $genemap2_File ne ""  ){


	if ($outDir eq "." || -d $outDir) {
		$workbookCoverage = Excel::Writer::XLSX->new( $outDir."/".$outPrefix."poorCoverage.xlsx" );
	}else {
 		die("No directory $outDir");
	}

	$worksheetCoverage = $workbookCoverage->add_worksheet('poor cov');
	$worksheetCoverage->freeze_panes( 1, 0 );    # Freeze the first row




	open(POORCOV , "<$poorCoverage_File") or die("Cannot open poorCoverage file ".$poorCoverage_File) ;
	print  STDERR "Processing poorCoverage file ... \n" ;

	while( <POORCOV> ){

  		$poorCoverage_Line = $_;

#############################################
##############   skip header
		chomp $poorCoverage_Line;

		@poorCoverage_List = split( /\t/, $poorCoverage_Line );

		if ($poorCoverage_Line=~/^#/){
			push @poorCoverage_List, "OMIM";
   			push @poorCoverage_List, "CANDIDATE";
      
		}else{

			#add OMIM phenotypes if exists => Assuming that gene name is in 4th column of poor coverage
			if (defined $genemap2_variant{$poorCoverage_List[3]}){
				push @poorCoverage_List, $genemap2_variant{$poorCoverage_List[3]} ;
			}else{
   				push @poorCoverage_List, "." ;
      			}
			
   			#add CANDIDATES TAG if exists => Assuming that gene name is in 4th column of poor coverage
   			if($candidates ne ""){
			
				if (defined $candidateGene{$poorCoverage_List[3]} ){
					
     					$candidateGene{$poorCoverage_List[3]}=~ s/CANDID_//g ;
					push @poorCoverage_List,  $candidateGene{$poorCoverage_List[3]} ;

				}else{
					push @poorCoverage_List, "." ;
				}	
			
			}else{

				push @poorCoverage_List, "." ;
				
			}
		}

		$worksheetCoverage->write_row($worksheetCoverageLine , 0, \@poorCoverage_List );
		$worksheetCoverageLine ++;

	}

	close(POORCOV);

	#############add autofilters within the sheets
	$worksheetCoverage->autofilter('A1:AZ'.$worksheetCoverageLine); # Add autofilter until the end

}



















print STDERR "Done!\n\n\n";

###################################################################
######################### FUNCTIONS ###############################
# Write in sheets
sub writeThisSheet {
	my ($worksheet,
		$worksheetLine,
		$format_pLI,
		$case,
		$hashTemp_ref,
		$hashColumn_ref) = @_;

	my %hashTemp = %{$hashTemp_ref};  #Dereference the hash
	my %hashColumn = %{$hashColumn_ref};

#						$hashTemp{'commentMPAscore'},
#						$hashTemp{'commentGnomADgenome'},
#						$hashTemp{'commentGnomADgenome'},
#						$hashTemp{'commentGenotype'},
#						$hashTemp{'commentFunc'},
#						$hashTemp{'commentPhenotype'},
#						$hashTemp{'commentPhenolyzer'},
#						$hashTemp{'commentInterVar'},
#						$hashTemp{'commentpLI'},
#						$hashTemp{'colorpLI'},
#						$hashTemp{'finalArray'},





	#dEBUG
#	print  "casecasecasecase         ". $hashTemp{'commentMPAscore'}."____".$hashColumn{"Gene.refGene"}."\n\n";

			#print STDERR "genotype case      ". $hashColumn{'Genotype-'.$case}."\n";
			#print STDERR "nb samples     ".$hashTemp{'nbSample'}."\n";

			$worksheet->write_row( $worksheetLine, 0, $hashTemp{'finalArray'} );
			$worksheet->write_comment( $worksheetLine,$hashColumn{'MPA_ranking'},		$hashTemp{'commentMPAscore'} ,x_scale => 2, y_scale => 5 );
			$worksheet->write_comment( $worksheetLine,$hashColumn{$gnomadGenomeColumn},	$hashTemp{'commentGnomADgenome'} ,x_scale => 3, y_scale => 2  );
			$worksheet->write_comment( $worksheetLine,$hashColumn{$gnomadExomeColumn},	$hashTemp{'commentGnomADexome'} ,x_scale => 3, y_scale => 2  );
			$worksheet->write_comment( $worksheetLine,$hashColumn{'Genotype-'.$case},	$hashTemp{'commentGenotype'} ,x_scale => 2, y_scale => $hashTemp{'nbSample'} );
			$worksheet->write_comment( $worksheetLine,$hashColumn{'MPA_impact'},		$hashTemp{'commentFunc'} ,x_scale => 3, y_scale => 3  );
			#$worksheet->write_comment( $worksheetLine,$hashColumn{'Func.'.$refGene},		$hashTemp{'commentFunc'} ,x_scale => 3, y_scale => 3  );

			#DEBUG print commentGenotype in CHROM cells
			#$worksheet->write_comment( $worksheetLine,$hashColumn{'#CHROM'},	$hashTemp{'commentGenotype'} ,x_scale => 2, y_scale => $hashTemp{'nbSample'} );


			if ($hashTemp{'commentPhenotype'} ne ""){

				$worksheet->write_comment( $worksheetLine,$hashColumn{'Phenotypes.'.$refGene}, $hashTemp{'commentPhenotype'} ,x_scale => 7, y_scale => 5  );
			}

			if ($hashTemp{'commentPhenolyzer'} ne ""){
				$worksheet->write_comment( $worksheetLine,$hashColumn{'Phenolyzer'}, $hashTemp{'commentPhenolyzer'} ,x_scale => 2 );
			}

			if ($hashTemp{'commentInterVar'} ne ""){
				$worksheet->write_comment( $worksheetLine,$hashColumn{'InterVar_automated'}, $hashTemp{'commentInterVar'} ,x_scale => 7, y_scale => 5  );
			}

			if ($hashTemp{'commentClinvar'} ne ""){
				$worksheet->write_comment( $worksheetLine,$hashColumn{'CLNSIG'}, $hashTemp{'commentClinvar'} ,x_scale => 7, y_scale => 5  );
			}


			if ($hashTemp{'commentpLI'} ne "."){

        		$format_pLI = $workbook->add_format(bg_color => $hashTemp{'colorpLI'});


				$worksheet->write( $worksheetLine,$hashColumn{'Gene.'.$refGene}, $hashTemp{'finalArray'}[$hashColumn{'Gene.'.$refGene}]     ,$format_pLI );
				$worksheet->write_comment( $worksheetLine,$hashColumn{'Gene.'.$refGene},$hashTemp{'commentpLI'},x_scale => 5, y_scale => 5  );
			}

			if(defined $hashTemp{'genotypeMozaic'} ){
				my @genotypeMozaic = split (';', $hashTemp{'genotypeMozaic'} );
				#recycling $format_pLI to color mozaic genotypes
				$format_pLI = $workbook->add_format(bg_color => 'purple');


				for( my $sampleMozaic = 0 ; $sampleMozaic < scalar @genotypeMozaic; $sampleMozaic +=2){
				#foreach my $sampleMozaic (@genotypeMozaic){
					$format_pLI = $workbook->add_format(bg_color => $genotypeMozaic[$sampleMozaic+1]);
					$worksheet->write( $worksheetLine,$hashColumn{$genotypeMozaic[$sampleMozaic]}  , $hashTemp{'finalArray'}[$hashColumn{$genotypeMozaic[$sampleMozaic]}] ,$format_pLI );
					#$worksheet->write( $worksheetLine,$hashColumn{$sampleMozaic}  , $hashTemp{'finalArray'}[$hashColumn{$sampleMozaic}] ,$format_pLI );
				}
			}
			# write URL  Mobidetails and franklin
			$worksheet->write( $worksheetLine,  $hashColumn{'MPA_impact'}  ,  $hashTemp{'MDurl'} , undef ,  $hashTemp{'finalArray'}[$hashColumn{'MPA_impact'}])  ;
			$worksheet->write( $worksheetLine,  $hashColumn{'#CHROMPOSREFALT'}  ,  $hashTemp{'Franklinurl'} , undef ,  $hashTemp{'finalArray'}[$hashColumn{'#CHROMPOSREFALT'}])  ;


}#END OF SUB

exit 0;