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Update predicates to handle special cases #1184

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Update predicates to handle special cases #1184

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8fc5aaa
Update predicates to handle special cases
nakib103 Sep 25, 2025
0a62c04
Overlap for insertions
nakib103 Oct 3, 2025
f2dcc69
typo
nakib103 Oct 3, 2025
cacb839
fix unit test
nakib103 Oct 4, 2025
90ede0e
Remove extra logic and update checking of final stop
nakib103 Oct 14, 2025
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37 changes: 22 additions & 15 deletions modules/Bio/EnsEMBL/Variation/Utils/VariationEffect.pm
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Original file line number Diff line number Diff line change
Expand Up @@ -1118,11 +1118,12 @@ sub inframe_insertion {
# we can use start_retained to check this
return 0 if start_retained_variant(@_) && $alt_pep =~ /\Q$ref_pep\E$/;

return 0 if $ref_pep eq "*" && $alt_pep eq "*"; # e.g. ref codon - TAG, alt codon - TAAG

# if we have a stop codon in the alt peptide
# trim off everything after it
# this allows us to detect inframe insertions that retain a stop
$alt_pep =~ s/\*.+/\*/;

return 1 if ($alt_pep =~ /^\Q$ref_pep\E/) || ($alt_pep =~ /\Q$ref_pep\E$/);

}
Expand Down Expand Up @@ -1250,7 +1251,7 @@ sub stop_lost {
# }

my ($ref_pep, $alt_pep) = _get_peptide_alleles(@_);
if(defined($ref_pep) && defined($alt_pep)) {
if(defined($ref_pep) && defined($alt_pep) && $alt_pep !~ 'X') {
$cache->{stop_lost} = ( ($alt_pep !~ /\*/) and ($ref_pep =~ /\*/) );
}
else {
Expand Down Expand Up @@ -1304,10 +1305,10 @@ sub stop_retained {

my ($ref_pep, $alt_pep) = _get_peptide_alleles(@_);

if(defined($alt_pep) && $alt_pep ne '') {
if(defined($alt_pep) && $alt_pep ne '' && $alt_pep !~ 'X') {

## handle inframe insertion of a stop just before the stop (no ref peptide)
$cache->{stop_retained} = ref_eq_alt_sequence(@_);
## handle inframe insertion of a stop just before the stop (no ref peptide)
$cache->{stop_retained} = ref_eq_alt_sequence(@_);
}
else {
$cache->{stop_retained} = ($pre->{increase_length} || $pre->{decrease_length}) && _overlaps_stop_codon(@_) && !_ins_del_stop_altered(@_);
Expand All @@ -1324,7 +1325,6 @@ sub ref_eq_alt_sequence {
$bvfo ||= $bvfoa->base_variation_feature_overlap;
my $ref_seq = $bvfo->_peptide;

my $mut_seq = $ref_seq;
my $tl_start = $bvfo->translation_start;
my $tl_end = $bvfo->translation_end;

Expand All @@ -1339,19 +1339,20 @@ sub ref_eq_alt_sequence {
# this is a logic from the former logic
return 1 if ($bvfoa->isa('Bio::EnsEMBL::Variation::TranscriptVariationAllele') && defined($ref_seq) && $tl_start > length($ref_seq) && $alt_pep =~ /^\*/);

my $mut_seq = $ref_seq;
substr($mut_seq, $tl_start-1, $tl_end - $tl_start + 1) = $alt_pep; # creating a mutated sequence from the ref sequence.

my $mut_substring = substr($mut_seq, 0, length($ref_seq)); # getting a substring up to the length of the ref sequence for comparison from index 0 to the length of the ref seq;

my $final_stop = substr($mut_seq, length($ref_seq)) if length($ref_seq) < length($mut_seq); # getting the length of the $mut_seq from the length of the ref_seq to the end

my $final_stop_length = length($final_stop) if defined($final_stop) ne '';

# 1 is if the ref_pep and the first letter of the alt_pep is the same and the alt_pep has * in it
# 2 is the ref_seq eq $mut_substring and the final stop length is less than 3
# 3 is * in ref_pep and the same index position exists for both the ref and alt pep
return 1 if ( ($ref_pep eq substr($alt_pep, 0, 1) && $alt_pep =~ /\*/) ||
($ref_seq eq $mut_substring && defined($final_stop_length) && $final_stop_length < 3) || ( $ref_pep =~ /\*/ && (index($ref_pep, "*") + 1 == index($alt_pep, "*") + 1) ));
# 1 is the ref_seq eq $mut_substring and the final stop is *
# 2 is * in ref_pep and the same index position exists for both the ref and alt pep
# print $final_stop, "\n";
return 1 if (
($ref_seq eq $mut_substring && defined($final_stop) && $final_stop =~ /^\Q*\E/) ||
($ref_pep =~ /\*/ && (index($ref_pep, "*") == index($alt_pep, "*")))
);
return 0;
}

Expand All @@ -1369,7 +1370,13 @@ sub _overlaps_stop_codon {

my ($cdna_start, $cdna_end) = ($bvfo->cdna_start, $bvfo->cdna_end);
return 0 unless $cdna_start && $cdna_end;


# for insertion add inserted seq length to see overlap
my $vf_feature_seq = $bvfoa->feature_seq;
$cdna_end = (($cdna_end < $cdna_start) && $vf_feature_seq =~ /^[ACTGN]+$/) ?
$cdna_start + length $vf_feature_seq :
$cdna_end;

$cache->{overlaps_stop_codon} = overlap(
$cdna_start, $cdna_end,
$feat->cdna_coding_end - 2, $feat->cdna_coding_end
Expand Down