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Merged
Peter-J-Freeman merged 3 commits into from
Mar 9, 2026
Merged

Develop #792

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b76f016
Updates that improve mapping of substitutions at the flanks of gaps. …
Peter-J-Freeman Mar 6, 2026
9a6a1af
Bug fix related to issue #786 and inclusion of test issue_786_part_A2…
Peter-J-Freeman Mar 6, 2026
60023ca
Merge pull request #791 from openvar/vcf_cnv
Peter-J-Freeman Mar 9, 2026
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1 change: 0 additions & 1 deletion VariantValidator/modules/gapped_mapping.py
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Original file line number Diff line number Diff line change
Expand Up @@ -2335,7 +2335,6 @@ def g_to_t_gap_compensation_version3(self, hgvs_alt_genomic, hgvs_coding, ori, a
if (rtx.posedit.pos.start.offset == 0 and rtx.posedit.pos.end.offset == 0) and (
ftx.posedit.pos.start.offset != 0 and ftx.posedit.pos.end.offset != 0):
exons = self.validator.hdp.get_tx_exons(ftx.ac, hgvs_not_delins.ac,
self.validator.alt_aln_method,
alt_aln_method=self.validator.alt_aln_method)
exonic = False
for ex_test in exons:
Expand Down
43 changes: 33 additions & 10 deletions VariantValidator/modules/vvMixinConverters.py
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Expand Up @@ -1122,33 +1122,57 @@ def myvm_t_to_g(self, hgvs_c, alt_chr, no_norm_evm, hn):
if 'Length implied by coordinates must equal sequence deletion length' in str(ea1):
# This will only happen if the variant is flanking the gap but is
# not inside the gap
logger.info('Variant is on the flank of a genomic gap but not within the gap')

# Logic, normalize the c. variant and if a substitution (cannot normalize) then direct map
# Currently believe that sub.n is the only variant type which fits. ins can normalize
# and may also be a dup! Added identity also
# and may also be a dup! Added identity also to non normalizing
try:
try:
norm_stored_c = hn.normalize(stored_hgvs_c)
except HGVSUnsupportedOperationError:
norm_stored_c = stored_hgvs_c

if norm_stored_c.posedit.edit.type == 'sub' or \
norm_stored_c.posedit.edit.type == 'identity':
flank_hgvs_genomic = self.vm.t_to_g(norm_stored_c, genomic_gap_variant.ac,
alt_aln_method)

flank_hgvs_genomic = self.vm.t_to_g(stored_hgvs_c, genomic_gap_variant.ac,
alt_aln_method)
init_flank_hgvs_genomic = copy.copy(flank_hgvs_genomic)

# Handle genomic opening gap (extra bases in transcript)
# Refer to test_inputs.py test_1 and test_2
if (len(flank_hgvs_genomic.posedit.edit.ref)
< len(stored_hgvs_c.posedit.edit.ref)
and
len(stored_hgvs_c.posedit.edit.ref) ==
len(genomic_gap_variant.posedit.edit.ref)-2
and
len(genomic_gap_variant.posedit.edit.ref) ==
len(genomic_gap_variant.posedit.edit.alt)):
n_flank_hgvs_genimic = hn.normalize(init_flank_hgvs_genomic)
if str(n_flank_hgvs_genimic) == str(init_flank_hgvs_genomic):
return self.vm.t_to_g(norm_stored_c, genomic_gap_variant.ac, alt_aln_method)
else:
return hn.normalize(init_flank_hgvs_genomic)
else:
flank_hgvs_genomic = self.vm.t_to_g(norm_stored_c, genomic_gap_variant.ac,
alt_aln_method)
self.vr.validate(flank_hgvs_genomic)

# Gap in the transcript
if (flank_hgvs_genomic.posedit.edit.type == 'sub' and
# Gap in the transcript e.g. NR2E3 tests
if (len(init_flank_hgvs_genomic.posedit.edit.ref)
> len(stored_hgvs_c.posedit.edit.ref)
and
len(stored_hgvs_c.posedit.edit.ref) ==
len(genomic_gap_variant.posedit.edit.ref) - 2):
return hn.normalize(init_flank_hgvs_genomic)
elif (flank_hgvs_genomic.posedit.edit.type == 'sub' and
norm_stored_c.posedit.edit.type == 'sub' and
stored_hgvs_c.posedit.edit.type == 'sub' and
# sub is a single base change
(len(genomic_gap_variant.posedit.edit.ref)+1 == (
genomic_gap_variant.posedit.pos.end.base -
genomic_gap_variant.posedit.pos.start.base + 1))):
pass
elif flank_hgvs_genomic.posedit.edit.type == 'sub':
return flank_hgvs_genomic
else:
return flank_hgvs_genomic

Expand Down Expand Up @@ -2672,7 +2696,6 @@ def transcript_filter(self, rts, select_transcripts=None):
# VF method
accession = str(k + "." + v["version"])
rts.append([accession] + v["list"])
print([accession] + v["list"])
return rts
# If we got select_transcripts as a json of tx convert it into a list
rts = []
Expand Down
90 changes: 57 additions & 33 deletions tests/test_inputs.py
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Expand Up @@ -28,18 +28,24 @@ def test_variant1(self):
'tlr': 'NP_055935.4:p.(Leu12Pro)', 'slr': 'NP_055935.4:p.(L12P)'}
assert results['NM_015120.4:c.35T>C']['hgvs_lrg_transcript_variant'] == 'LRG_741t1:c.35T>C'
assert results['NM_015120.4:c.35T>C']['hgvs_lrg_variant'] == 'LRG_741:g.5146T>C'
assert results['NM_015120.4:c.35T>C']['primary_assembly_loci']['hg19'] == {
'hgvs_genomic_description': 'NC_000002.11:g.73613031T>C',
'vcf': {'chr': 'chr2', 'pos': '73613031', 'ref': 'T', 'alt': 'C'}}
assert results['NM_015120.4:c.35T>C']['primary_assembly_loci']['hg38'] == {
'hgvs_genomic_description': 'NC_000002.12:g.73385903T>C',
'vcf': {'chr': 'chr2', 'pos': '73385903', 'ref': 'T', 'alt': 'C'}}
assert results['NM_015120.4:c.35T>C']['primary_assembly_loci']['grch37'] == {
'hgvs_genomic_description': 'NC_000002.11:g.73613031T>C',
'vcf': {'chr': '2', 'pos': '73613031', 'ref': 'T', 'alt': 'C'}}
"hgvs_genomic_description": "NC_000002.11:g.73613031delinsCGGA",
"vcf": {
"alt": "CGGA",
"chr": "2",
"pos": "73613031",
"ref": "T"
}
}
assert results['NM_015120.4:c.35T>C']['primary_assembly_loci']['grch38'] == {
'hgvs_genomic_description': 'NC_000002.12:g.73385903T>C',
'vcf': {'chr': '2', 'pos': '73385903', 'ref': 'T', 'alt': 'C'}}
"hgvs_genomic_description": "NC_000002.12:g.73385903delinsCGGA",
"vcf": {
"alt": "CGGA",
"chr": "2",
"pos": "73385903",
"ref": "T"
}
}
assert results['NM_015120.4:c.35T>C']['reference_sequence_records'] == {
'transcript': 'https://www.ncbi.nlm.nih.gov/nuccore/NM_015120.4',
'protein': 'https://www.ncbi.nlm.nih.gov/nuccore/NP_055935.4',
Expand All @@ -65,18 +71,24 @@ def test_variant2(self):
'tlr': 'NP_055935.4:p.(Glu13Asp)', 'slr': 'NP_055935.4:p.(E13D)'}
assert results['NM_015120.4:c.39G>C']['hgvs_lrg_transcript_variant'] == 'LRG_741t1:c.39G>C'
assert results['NM_015120.4:c.39G>C']['hgvs_lrg_variant'] == 'LRG_741:g.5150G>C'
assert results['NM_015120.4:c.39G>C']['primary_assembly_loci']['hg19'] == {
'hgvs_genomic_description': 'NC_000002.11:g.73613032G>C',
'vcf': {'chr': 'chr2', 'pos': '73613032', 'ref': 'G', 'alt': 'C'}}
assert results['NM_015120.4:c.39G>C']['primary_assembly_loci']['hg38'] == {
'hgvs_genomic_description': 'NC_000002.12:g.73385904G>C',
'vcf': {'chr': 'chr2', 'pos': '73385904', 'ref': 'G', 'alt': 'C'}}
assert results['NM_015120.4:c.39G>C']['primary_assembly_loci']['grch37'] == {
'hgvs_genomic_description': 'NC_000002.11:g.73613032G>C',
'vcf': {'chr': '2', 'pos': '73613032', 'ref': 'G', 'alt': 'C'}}
"hgvs_genomic_description": "NC_000002.11:g.73613034_73613035insCGA",
"vcf": {
"alt": "GGAC",
"chr": "2",
"pos": "73613032",
"ref": "G"
}
}
assert results['NM_015120.4:c.39G>C']['primary_assembly_loci']['grch38'] == {
'hgvs_genomic_description': 'NC_000002.12:g.73385904G>C',
'vcf': {'chr': '2', 'pos': '73385904', 'ref': 'G', 'alt': 'C'}}
"hgvs_genomic_description": "NC_000002.12:g.73385906_73385907insCGA",
"vcf": {
"alt": "GGAC",
"chr": "2",
"pos": "73385904",
"ref": "G"
}
}
assert results['NM_015120.4:c.39G>C']['reference_sequence_records'] == {
'transcript': 'https://www.ncbi.nlm.nih.gov/nuccore/NM_015120.4',
'protein': 'https://www.ncbi.nlm.nih.gov/nuccore/NP_055935.4',
Expand Down Expand Up @@ -3665,16 +3677,10 @@ def test_variant76(self):

# Bug fix for issue https://github.com/openvar/variantValidator/issues/94 creates extra outputs. Not an issue so ignore
# self.assertCountEqual(results['NM_032790.3:c.126C>A']['alt_genomic_loci'], [{'grch37': {'hgvs_genomic_description': 'NW_004504303.2:g.302871_302876del', 'vcf': {'chr': 'HG1595_PATCH', 'pos': '302869', 'ref': 'GCCCCGC', 'alt': 'G'}}}, {'hg19': {'hgvs_genomic_description': 'NW_004504303.2:g.302871_302876del', 'vcf': {'chr': 'NW_004504303.2', 'pos': '302869', 'ref': 'GCCCCGC', 'alt': 'G'}}}])
assert results['NM_032790.3:c.126C>A']['primary_assembly_loci']['hg19'] == {
'hgvs_genomic_description': 'NC_000012.11:g.122064773C>A',
'vcf': {'chr': 'chr12', 'pos': '122064773', 'ref': 'C', 'alt': 'A'}}
assert results['NM_032790.3:c.126C>A']['primary_assembly_loci']['hg38'][
'hgvs_genomic_description'] == 'NC_000012.12:g.121626873C>A'
assert results['NM_032790.3:c.126C>A']['primary_assembly_loci']['grch37'] == {
'hgvs_genomic_description': 'NC_000012.11:g.122064773C>A',
'vcf': {'chr': '12', 'pos': '122064773', 'ref': 'C', 'alt': 'A'}}
assert results['NM_032790.3:c.126C>A']['primary_assembly_loci']['grch37'][
'hgvs_genomic_description'] == 'NC_000012.11:g.122064773_122064778del'
assert results['NM_032790.3:c.126C>A']['primary_assembly_loci']['grch38'][
'hgvs_genomic_description'] == 'NC_000012.12:g.121626873C>A'
'hgvs_genomic_description'] == 'NC_000012.12:g.121626868_121626873delinsA'
assert results['NM_032790.3:c.126C>A']['reference_sequence_records'] == {
'transcript': 'https://www.ncbi.nlm.nih.gov/nuccore/NM_032790.3',
'protein': 'https://www.ncbi.nlm.nih.gov/nuccore/NP_116179.2',
Expand Down Expand Up @@ -31089,21 +31095,21 @@ def test_issue_651a(self):
variant = 'NM_017680.6:c.153G>T'
select_transcripts = 'all'
results = self.vv.validate(variant, 'GRCh38', select_transcripts).format_as_dict(test=True)
assert 'NC_000009.12:g.92474742delinsATCA' in \
assert 'NC_000009.12:g.92474742_92474744del' in \
results['NM_017680.6:c.153G>T'][
'primary_assembly_loci']['grch38']['hgvs_genomic_description']
assert 'NC_000009.11:g.95237024delinsATCA' in \
assert 'NC_000009.11:g.95237024_95237026del' in \
results['NM_017680.6:c.153G>T'][
'primary_assembly_loci']['grch37']['hgvs_genomic_description']

def test_issue_651b(self):
variant = 'NC_000009.12:g.92474742delinsATCA'
select_transcripts = 'NM_017680.6'
results = self.vv.validate(variant, 'GRCh38', select_transcripts).format_as_dict(test=True)
assert 'NC_000009.12:g.92474742delinsATCA' in \
assert 'NC_000009.12:g.92474742_92474744del' in \
results['NM_017680.6:c.153G>T'][
'primary_assembly_loci']['grch38']['hgvs_genomic_description']
assert 'NC_000009.11:g.95237024delinsATCA' in \
assert 'NC_000009.11:g.95237024_95237026del' in \
results['NM_017680.6:c.153G>T'][
'primary_assembly_loci']['grch37']['hgvs_genomic_description']

Expand Down Expand Up @@ -31271,6 +31277,24 @@ def issue_786_part_B(self):
assert results["intergenic_variant_1"]["primary_assembly_loci"]["grch38"][
"hgvs_genomic_description"] == "NC_000023.11:g.18890210_18893706delinsGCCTGCAGAG"

def issue_786_part_A1(self):
# Test that it fails for genome mismatch
results = self.vv.validate('NC_000015.9:g.72105928del', 'GRCh37', 'mane_select', liftover_level=True).format_as_dict(test=True)
assert 'intergenic_variant_1' in results
assert results["NM_014249.4:c.947A>C"]["primary_assembly_loci"]["grch37"][
"hgvs_genomic_description"] == "NC_000015.9:g.72105928del"
assert results["NM_014249.4:c.947A>C"]["primary_assembly_loci"]["grch38"][
"hgvs_genomic_description"] == "NC_000015.10:g.71813588A>C"

def issue_786_part_A2(self):
# Test that it fails for genome mismatch
results = self.vv.validate('NC_000015.9:g.72105933dup', 'GRCh37', 'mane_select', liftover_level=True).format_as_dict(test=True)
assert 'intergenic_variant_1' in results
assert results["NM_014249.4:c.947A>C"]["primary_assembly_loci"]["grch37"][
"hgvs_genomic_description"] == "NC_000015.9:g.72105933dup"
assert results["NM_014249.4:c.947A>C"]["primary_assembly_loci"]["grch38"][
"hgvs_genomic_description"] == "NC_000015.10:g.71813591_71813592dup"


# <LICENSE>
# Copyright (C) 2016-2026 VariantValidator Contributors
Expand Down