#!/usr/bin/env perl
use strict;
#use warnings;
use List::Util qw(sum);

die "useage:perl $0 input project sample_type somtic_out germline_out tag_out " unless @ARGV == 6;
my ($input, $project, $sample_type, $somtic_out, $germline_out, $tag_out) = @ARGV;

# die "useage:perl $0 output_dir tumor project sample_type" unless @ARGV == 4;
# my ($output_dir, $name, $project, $sample_type) = @ARGV;

# open IN, "$output_dir/mutation/${name}.snp.indel.anno.hg19_multianno.txt";
open IN, "$input";
my $head = <IN>;
# if ($sample_type eq 'c') {
#     open OUT, ">${name}.snp.indel.Somatic.annoall.hg19_multianno_filtered_pre.txt";
# }
# elsif ($sample_type eq 't') {
#     open OUT, ">${name}.snp.indel.Somatic.annoall.hg19_multianno_filtered.txt";
# }

open OUT, "> $somtic_out";
print OUT "可信\t$head";

# open OUT2, ">${name}.snp.indel.Germline.anno.hg19_multianno_filtered.txt";
open OUT2, ">$germline_out";
print OUT2 "临床意义\t$head";

# open OUT3, ">${name}.snp.indel.anno.hg19_multianno_tag.txt";
open OUT3, ">$tag_out";
print OUT3 "TAG\t$head";

##black list
my $public_path = defined $ENV{'PUBLIC'} ? $ENV{'PUBLIC'} : "/dataseq/jmdna/codes/public/";
open BKLT, "$public_path/blacklist.txt";
my %bk;
<BKLS>;
while (<BKLT>) {
    chomp;
    my @line = split("\t");
    my $key = join("_", @line[0 .. 4]);
    $bk{$key} = 1;
}
sub blacklist {
    my $pos = shift @_;
    if (exists $bk{$pos}) {
        return "1";
    }
    else {
        return "";
    }
}

open INFO, "$public_path/info.txt";
my @muts;
while (<INFO>) {
    chomp;
    my @line = split(/\t/, $_);
    if ($line[0] eq $project) {
        if ($line[2] ne "NA") {
            @muts = split(/\//, $line[2]);
        }
    }
}

while (<IN>) {
    chomp;
    my @line = split(/\t/, $_);
    my $freq = (split(":", $line[-1]))[4];
    #	next if $line[9] eq '.';
    if ($line[8] ne "synonymous SNV" and $line[8] ne "unknown") {
        if ($line[17] < 0.01 and $line[18] < 0.01 and $line[19] < 0.01 and $line[20] < 0.01 and $line[23] < 0.01 and $line[28] < 0.01 and $line[32] < 0.01) {
            if ($line[16] =~ /benign/i and $line[16] !~ /pathogenic|Affects|association|Conflicting|sensitivity|drug|other|risk|protective|Uncertain|not_provided|\./i) {
                print OUT3 "benign\t", join("\t", @line), "\n";
                next;
            }
            if ($sample_type eq 'c') {
                if ($line[11] =~ /OCCURENCE=(\S+)/) {
                    my $cosmic = $1;
                    $cosmic =~ s/\(\S+?\)//g;
                    my @cosmic = split(",", $cosmic);
                    $cosmic = sum @cosmic;
                    if ($freq < 0.01 and $cosmic <= 1) {
                        print OUT3 "cfdna_lowfreq_cosmic\t", join("\t", @line), "\n";
                        next;
                    }
                }
                if ($freq < 0.01 and $line[11] eq '.') {
                    print OUT3 "cfdna_lowfreq_cosmic\t", join("\t", @line), "\n";
                    next;
                }
            }
            #blacklist
            my $key = join("_", @line[0 .. 4]);
            if (&blacklist($key)) {
                print OUT3 "blacklist\t", join("\t", @line), "\n";
                next;
            };
            if ($line[9] ne '.') {
                my @hgvs = split(/,/, $line[9]);
                my $hgvs = $hgvs[0];
                $hgvs =~ /(\S+):(\S+):exon(\d+):c\.(\S+):p\.(\S+)$/;
                my $gene = $1;
                if (!(@muts and grep {$gene eq $_} @muts)) {
                    print OUT3 "nontarget_gene\t", join("\t", @line), "\n";
                    next;
                }

                if ($line[101] ne 'PASS') {
                    my $filter = split(";", $line[101]);
                    if ($freq < 0.02 or ($freq >= 0.02 and $freq < 0.05 and $filter >= 2)) {
                        print OUT3 "byfilter\t", join("\t", @line), "\n";
                        next;
                    };
                }
                if (my $transcript = &transcript($gene)) {
                    if (grep {/$transcript/} @hgvs) {
                        $hgvs = (grep {/$transcript/} @hgvs)[0];
                    }
                }
                $line[9] = $hgvs;

                print OUT "1\t", join("\t", (@line[0 .. 4], "exonic", $gene, @line[7 .. $#line])), "\n";
                print OUT3 "PASS\t", join("\t", @line), "\n";

                if ($freq > 0.1) {
                    if ($line[16] =~ /Likely_pathogenic|drug/i) {
                        print OUT2 "2\t", join("\t", (@line[0 .. 4], "exonic", $gene, @line[7 .. $#line])), "\n";
                    }
                    elsif ($line[16] =~ /pathogenic/i and $line[16] !~ /Conflicting/i) {
                        print OUT2 "1\t", join("\t", (@line[0 .. 4], "exonic", $gene, @line[7 .. $#line])), "\n";
                    }
                    else {
                        print OUT2 "3\t", join("\t", (@line[0 .. 4], "exonic", $gene, @line[7 .. $#line])), "\n";
                    }
                }
            }

            elsif ($line[5] =~ /splicing/) {
                # next if $line[101] ne 'PASS';
                # if ($line[101] ne 'PASS') {
                #     print OUT3 "unknow3\t", join("\t", @line), "\n";
                #     next;
                # }
                my $gene = (split(";", $line[6]))[0];
                if (!(@muts and grep {$gene eq $_} @muts)) {
                    print OUT3 "nontarget_gene\t", join("\t", @line), "\n";
                    next;
                };
                my @hgvs = split(/;/, $line[7]);
                my $hgvs = $hgvs[0];
                if (my $transcript = &transcript($gene)) {
                    if (grep {/$transcript/} @hgvs) {
                        $hgvs = (grep {/$transcript/} @hgvs)[0];
                    }
                }
                $hgvs =~ /(\S+):exon(\d+):c\.(\S+)$/;
                my $spl = $3;

                if ($spl =~ /\d+[\+|\-][1|2]\D+/) {
                    $line[7] = join(":", ($gene, $hgvs));
                    print OUT3 "PASS\t", join("\t", @line), "\n";
                    print OUT "1\t", join("\t", (@line[0 .. 4], "splicing", $gene, '.', '.', @line[7, 10 .. $#line])), "\n";
                    if ($freq > 0.1) {
                        if ($line[16] =~ /Likely_pathogenic|drug/i) {
                            print OUT2 "2\t", join("\t", (@line[0 .. 4], "splicing", $gene, '.', '.', @line[7, 10 .. $#line])), "\n";
                        }
                        elsif ($line[16] =~ /pathogenic/i and $line[16] !~ /Conflicting/i) {
                            print OUT2 "1\t", join("\t", (@line[0 .. 4], "splicing", $gene, '.', '.', @line[7, 10 .. $#line])), "\n";
                        }
                        else {
                            print OUT2 "3\t", join("\t", (@line[0 .. 4], "splicing", $gene, '.', '.', @line[7, 10 .. $#line])), "\n";
                        }
                    }
                }
                else {
                    print OUT3 "unknow1\t", join("\t", @line), "\n";
                }

            }
            else {
                print OUT3 "unknow2\t", join("\t", @line), "\n";
            }
        }
        else {
            print OUT3 "common_snp\t", join("\t", @line), "\n";
        }
    }
    else {
        print OUT3 "synonymous\t", join("\t", @line), "\n";
    }
}

sub transcript {
    my $gene = shift @_;
    my $data_path = defined $ENV{'DATABASE'} ? $ENV{'DATABASE'} : "/dataseq/jmdna/codes/reportbase/";
    open TR, "$data_path/oncokbgene.txt";
    my %oncogene;
    while (<TR>) {
        chomp;
        my @line = split;
        $oncogene{$line[0]} = $line[2];
    }
    if (exists $oncogene{$gene}) {
        $oncogene{$gene} =~ s/\.\d+//;
        return $oncogene{$gene};
    }
    else {
        print "$gene has no NM id in oncokbgene.txt";
        return "";
    }
}