Develop

VariantValidator/modules/gapped_mapping.py

@@ -1864,6 +1864,9 @@ def g_to_t_compensation(self, ori, hgvs_coding, rec_var):
                     hgvs_genomic.posedit.pos.end.base = start
                     hgvs_genomic = self.variant.hn.normalize(hgvs_genomic)
 
+        logger.info(f"g_to_t_compensation returning hgvs_genomic {hgvs_genomic }hgvs_coding {hgvs_coding}, "
+                    f"suppress c normalization {suppress_c_normalization}")
+
         return hgvs_genomic, suppress_c_normalization, hgvs_coding
 
     def g_to_t_gapped_mapping_stage2(self, ori, hgvs_coding, hgvs_genomic):
@@ -2002,14 +2005,17 @@ def g_to_t_gapped_mapping_stage2(self, ori, hgvs_coding, hgvs_genomic):
             else:
                 hgvs_coding = copy.deepcopy(hgvs_refreshed_variant)
 
+        logger.info(f"g_to_t_gaped_mapping_stage2 returning hgvs_coding {hgvs_coding}")
         return hgvs_coding
 
     def g_to_t_gap_compensation_version3(self, hgvs_alt_genomic, hgvs_coding, ori, alt_chr, rec_var):
 
         self.orientation = int(ori[0]['alt_strand'])
         hgvs_genomic = copy.deepcopy(hgvs_alt_genomic)
 
-        logger.debug('g_to_t gap code 3 active')
+        logger.debug(f"g_to_t_gap_compensation_version3 triggered with hgvs_alt_genomic {hgvs_alt_genomic},"
+                    f" hgvs_coding {hgvs_coding}, alt_chr {alt_chr}, rec_var {rec_var}, ori {ori}")
+
         rn_hgvs_genomic = self.variant.reverse_normalizer.normalize(hgvs_alt_genomic)
         self.hgvs_genomic_possibilities.append([rn_hgvs_genomic, ['false', 'false']])
         if self.orientation != -1:
@@ -2712,6 +2718,8 @@ def g_to_t_gap_compensation_version3(self, hgvs_alt_genomic, hgvs_coding, ori, a
         except UnboundLocalError:
             pass
 
+        logger.debug(f"g_to_t_gap_compensation_version3 returning hgvs_genomic {hgvs_genomic}, "
+                    f"hgvs_coding {hgvs_coding}")
         return hgvs_alt_genomic, hgvs_coding
 
     def dup_ins_5prime_shift(self, stored_hgvs_not_delins, saved_hgvs_coding):
@@ -2984,8 +2992,11 @@ def transcript_disparity(self, reverse_normalized_hgvs_genomic, stored_hgvs_not_
                 c_tx_hgvs_not_delins = self.validator.vm.n_to_c(self.tx_hgvs_not_delins)
             except Exception:
                 c_tx_hgvs_not_delins = copy.copy(self.tx_hgvs_not_delins)
-            genomic_gap_fill_variant_alt = self.validator.vm.t_to_g(c_tx_hgvs_not_delins, self.hgvs_genomic_5pr.ac,
-                                                                    alt_aln_method=self.validator.alt_aln_method)
+            genomic_gap_fill_variant_alt = self.validator.myvm_t_to_g(c_tx_hgvs_not_delins,
+                                                                      self.hgvs_genomic_5pr.ac,
+                                                                      self.variant.no_norm_evm,
+                                                                      self.variant.hn,
+                                                                      self.variant.map_dat)
 
             # Ensure an ALT exists
             try:

VariantValidator/modules/mappers.py

@@ -1040,12 +1040,12 @@ def final_tx_to_multiple_genomic(variant, validator, tx_variant, liftover_level=
             # Loop out gap code under these circumstances!
             if variant.map_dat.is_gapped_map(variant.hgvs_coding.ac,hgvs_alt_genomic.ac,validator):
                 # warn on gap_compensation for
-                logger.debug("gap_compensation_3 done for %s when mapped to %s" %
-                             (variant.hgvs_coding.ac, hgvs_alt_genomic.ac))
                 gap_mapper = gapped_mapping.GapMapper(variant, validator)
                 hgvs_alt_genomic, hgvs_coding = gap_mapper.g_to_t_gap_compensation_version3(
                     hgvs_alt_genomic, variant.hgvs_coding, ori, alt_chr, rec_var)
+                logger.info(f"gap_compensation_3 done for {variant.hgvs_coding} mapped to {hgvs_alt_genomic}")
                 variant.hgvs_coding = hgvs_coding
+                logger.info(f"hgvs_coding updated to {hgvs_coding}")
 
                 # Check for mismatched sequence in dup variants
                 if hgvs_alt_genomic.posedit.edit.type == hgvs_coding.posedit.edit.type and \

VariantValidator/modules/transcript_map_data.py

@@ -1,4 +1,8 @@
 import copy
+import logging
+
+logger = logging.getLogger(__name__)
+
 """
 A module for holding the TranscriptMapData specific to an individual transcript
 in order to avoid having to repeatedly re-pull from the database.
@@ -22,6 +26,9 @@ def __init__(self,hdp=None):
         self.mapped_strands = {} # made using above map data, for dict fetch
         self.mapping_types = {} # the mapping type for each tx->alt map
         self.exon_data = {} # the set of exon data per mapping
+        self._known_bad_alignments = [
+            ["NM_001009944.3", "NT_187607.1"]
+        ]
 
     def mapping_options(self,tx_ac,hdp=None):
         """
@@ -45,6 +52,14 @@ def mapping_options(self,tx_ac,hdp=None):
                     "provider (hdp) for use as a data source")
         self.mapping_opts[tx_ac] = cur_hdp.get_tx_mapping_options(
                 tx_ac,gap_warn=True)
+
+        self.mapping_opts[tx_ac] = [
+            option
+            for option in self.mapping_opts[tx_ac]
+            if [option[0], option[1]] not in self._known_bad_alignments
+        ]
+
+        logger.info(f"Mapping options for {tx_ac}: {self.mapping_opts[tx_ac]}")
         return self.mapping_opts[tx_ac]
 
     def map_strand(self,tx_ac,alt_ac,hdp=None):
@@ -157,7 +172,9 @@ def tx_exons(self, tx_ac, alt_ac, alt_aln_method, hdp=None):
         # If on the reverse strand, reverse the order of elements
         if tx_exons[0]['alt_strand'] == -1:
             tx_exons = tx_exons[::-1]
+            logger.debug(f"Exon data for {tx_ac}: {tx_exons}")
             return tx_exons
         else:
+            logger.debug(f"Exon data for {tx_ac}: {tx_exons}")
             return tx_exons
 

VariantValidator/modules/variant.py

@@ -23,6 +23,7 @@ def __init__(self, original, quibble=None, warnings=None, write=True, primary_as
         self.input_parses = None  # quibble as hgvs variant object
         self.transcript_type = None
         self.lovd_syntax_check = None
+        self.shorthand_vcf = None
         self.lovd_messages = None
         self.lovd_corrections = None
 

VariantValidator/modules/vvMixinConverters.py

@@ -1096,7 +1096,7 @@ def myvm_t_to_g(self, hgvs_c, alt_chr, no_norm_evm, hn, map_dat):
             hgvs_genomic.posedit.edit.alt = hgvs_genomic.posedit.edit.ref
         if hgvs_genomic.posedit.edit.type == 'ins' and utilise_gap_code is True:
             try:
-                pre_norm_genomic = copy.copy(hgvs_genomic)# can move ins variants (and in doing so break mid base == original bases assumption)
+                pre_norm_genomic = copy.copy(hgvs_genomic) # can move ins variants (and in doing so break mid base == original bases assumption)
                 hgvs_genomic = hn.normalize(hgvs_genomic)
                 if stored_hgvs_c.posedit.edit.alt and len(stored_hgvs_c.posedit.edit.alt) + 2 == \
                         len(hgvs_c.posedit.edit.alt) and hgvs_c.posedit.edit.alt == pre_norm_genomic.posedit.edit.alt:
@@ -1119,6 +1119,14 @@ def myvm_t_to_g(self, hgvs_c, alt_chr, no_norm_evm, hn, map_dat):
                     hgvs_genomic.posedit.pos.end.base = start
                     hgvs_genomic = hn.normalize(hgvs_genomic)
 
+            except AttributeError as e:
+                if "'Dup' object has no attribute 'alt'" in str(e):
+                    logger.error(
+                        f"Code triggered previously in very poor alignment so not able to fully test, refer to "
+                        f"test_inputs.py tests test_alt_gapping_bug: "
+                        f"hgvs_genomic: {hgvs_genomic}, stored_hgvs_c: {stored_hgvs_c}")
+                    raise
+
         # Statements required to reformat the stored_hgvs_c into a useable synonym
         if (stored_hgvs_c.posedit.edit.ref == '' or stored_hgvs_c.posedit.edit.ref is None) and expand_out:
             if stored_hgvs_c.type == 'c':
@@ -1396,6 +1404,7 @@ def myvm_t_to_g(self, hgvs_c, alt_chr, no_norm_evm, hn, map_dat):
                     hgvs_genomic = hn.normalize(hgvs_genomic)
                 except:
                     pass
+
         # Correct expansion ref + 2
         elif expand_out and (
                 len(hgvs_genomic.posedit.edit.ref) == (len(stored_hgvs_c.posedit.edit.ref) + 2)):  # >= 3:

VariantValidator/modules/vvMixinCore.py

@@ -49,7 +49,8 @@ def validate(self,
                  select_transcripts,
                  transcript_set=None,
                  liftover_level=False,
-                 lovd_syntax_check=False):
+                 lovd_syntax_check=False,
+                 shorthand_vcf=False):
         """
         This is the main validator function.
         :param batch_variant: A string containing the variant to be validated
@@ -59,6 +60,7 @@ def validate(self,
         Selecting multiple transcripts will lead to a multiple variant outputs.
         :param transcript_set: 'refseq' or 'ensembl'
         :param lovd_syntax_check: True or False
+        :param shorthand_vcf: True or False
         :return:
         """
         logger.debug("Running validate with inputs %s and assembly %s", batch_variant, selected_assembly)
@@ -78,6 +80,9 @@ def validate(self,
         self.selected_assembly = selected_assembly
         self.select_transcripts = select_transcripts
 
+        # Set output VCF format
+        self.shorthand_vcf = shorthand_vcf
+
         # Set LOVD syntax checker
         self.lovd_syntax_check = lovd_syntax_check
 
@@ -1607,11 +1612,13 @@ def _apply_met_variation(data):
                 else:
                     variant.hgvs_refseqgene_variant = ''
                 hgd = "hgvs_genomic_description"
-                def _vcf_abrv(hgvs,vcf,max_non_abrv_len=100):
+                def _vcf_abrv(hgvs,vcf,max_non_abrv_len=500):
                     """
                     Abbreviate long del/dup/ins type vcf
                     Use start-stop as pos ref N alt as type,
                     not pos as start ref and alt as (extra long seq"""
+                    if self.shorthand_vcf is False:
+                        return vcf
                     try:
                         # only shorten vcf if ref based and long
                         # (and not uncertain which should not have vcf data)

tests/test_gene2transcript.py

@@ -169,13 +169,18 @@ def test_select_transcripts(self):
         output_d = self.vv.gene2transcripts('BRCA2', select_transcripts='flibble')
         output_e = self.vv.gene2transcripts('BRAF', select_transcripts='mane_select')
         output_f = self.vv.gene2transcripts('BRAF', select_transcripts='mane')
+        output_g = self.vv.gene2transcripts('BRCA2', select_transcripts='all')
+        output_h = self.vv.gene2transcripts('BRCA2', select_transcripts='raw')
+
         print(output)
         assert len(output['transcripts']) >= 3
         assert len(output_b['transcripts']) == 1
         assert len(output_c['transcripts']) == 2
         assert len(output_d['transcripts']) == 0
         assert len(output_e['transcripts']) == 1
         assert len(output_f['transcripts']) >= 2
+        assert (len(output_b['transcripts']) < len(output_c['transcripts']) < len(output_g['transcripts'])
+                < len(output_h['transcripts']))
 
     def test_symbol_valid_hgnc_id(self):
         symbol = 'HGNC:2197'

tests/test_inputs.py

@@ -1159,7 +1159,7 @@ def test_variant20(self):
 
     def test_variant21(self):
         variant = 'NM_000518.4:c.316_*100del'
-        results = self.vv.validate(variant, 'GRCh37', 'all').format_as_dict(test=True)
+        results = self.vv.validate(variant, 'GRCh37', 'all', shorthand_vcf=True).format_as_dict(test=True)
         print(results)
 
         assert results['flag'] == 'gene_variant'
@@ -1178,13 +1178,37 @@ def test_variant21(self):
         assert results['NM_000518.4:c.316_*100del']['hgvs_lrg_variant'] == ''
         self.assertCountEqual(results['NM_000518.4:c.316_*100del']['alt_genomic_loci'], [])
         assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['hg19'] == {
-            'hgvs_genomic_description': 'NC_000011.9:g.5246728_5246956del', 'vcf': {'alt': 'DEL', 'chr': 'chr11', 'pos': '5246728-5246956', 'ref': 'N'}}
-        assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['hg38'] == {
-            'hgvs_genomic_description': 'NC_000011.10:g.5225498_5225726del', 'vcf': {'alt': 'DEL', 'chr': 'chr11', 'pos': '5225498-5225726', 'ref': 'N'}}
-        assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['grch37'] == {
-            'hgvs_genomic_description': 'NC_000011.9:g.5246728_5246956del', 'vcf': {'alt': 'DEL', 'chr': '11', 'pos': '5246728-5246956', 'ref': 'N'}}
+                "hgvs_genomic_description": "NC_000011.9:g.5246728_5246956del",
+                "vcf": {
+                    "alt": "A",
+                    "chr": "chr11",
+                    "pos": "5246727",
+                    "ref": "AATCCAGATGCTCAAGGCCCTTCATAATATCCCCCAGTTTAGTAGTTGGACTTAGGGAACAAAGGAACCTTTAATAGAAATTGGACAGCAAGAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCCCAGGAG"
+                }}
+        assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['hg38'] ==  {
+                "hgvs_genomic_description": "NC_000011.10:g.5225498_5225726del",
+                "vcf": {
+                    "alt": "A",
+                    "chr": "chr11",
+                    "pos": "5225497",
+                    "ref": "AATCCAGATGCTCAAGGCCCTTCATAATATCCCCCAGTTTAGTAGTTGGACTTAGGGAACAAAGGAACCTTTAATAGAAATTGGACAGCAAGAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCCCAGGAG"
+                }}
+        assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['grch37'] ==  {
+                "hgvs_genomic_description": "NC_000011.9:g.5246728_5246956del",
+                "vcf": {
+                    "alt": "A",
+                    "chr": "11",
+                    "pos": "5246727",
+                    "ref": "AATCCAGATGCTCAAGGCCCTTCATAATATCCCCCAGTTTAGTAGTTGGACTTAGGGAACAAAGGAACCTTTAATAGAAATTGGACAGCAAGAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCCCAGGAG"
+                }}
         assert results['NM_000518.4:c.316_*100del']['primary_assembly_loci']['grch38'] == {
-            'hgvs_genomic_description': 'NC_000011.10:g.5225498_5225726del', 'vcf': {'alt': 'DEL', 'chr': '11', 'pos': '5225498-5225726', 'ref': 'N'}}
+                "hgvs_genomic_description": "NC_000011.10:g.5225498_5225726del",
+                "vcf": {
+                    "alt": "A",
+                    "chr": "11",
+                    "pos": "5225497",
+                    "ref": "AATCCAGATGCTCAAGGCCCTTCATAATATCCCCCAGTTTAGTAGTTGGACTTAGGGAACAAAGGAACCTTTAATAGAAATTGGACAGCAAGAAAGCGAGCTTAGTGATACTTGTGGGCCAGGGCATTAGCCACACCAGCCACCACTTTCTGATAGGCAGCCTGCACTGGTGGGGTGAATTCTTTGCCAAAGTGATGGGCCAGCACACAGACCAGCACGTTGCCCAGGAG"
+                }}
         assert results['NM_000518.4:c.316_*100del']['reference_sequence_records'] == {
             'transcript': 'https://www.ncbi.nlm.nih.gov/nuccore/NM_000518.4',
             'protein': 'https://www.ncbi.nlm.nih.gov/nuccore/NP_000509.1',
@@ -30368,7 +30392,7 @@ def test_variant333(self):
 
     def test_variant334(self):
         variant = 'NM_000061.2:c.588_589insCTACATAG'
-        results = self.vv.validate(variant, 'GRCh37', 'all').format_as_dict(test=True)
+        results = self.vv.validate(variant, 'GRCh37', 'all', shorthand_vcf=True).format_as_dict(test=True)
         print(results)
 
         assert results['flag'] == 'gene_variant'
@@ -31304,7 +31328,7 @@ def test_issue_733a(self):
         results = self.vv.validate('chr11:118650341:C:T', 'GRCh37','NM_004397.6').format_as_dict(test=True)
         assert 'NM_004397.6:c.369G>A' in results
 
-    def polyadenylation_a(self):
+    def test_polyadenylation_a(self):
         # Test that it fails for genome mismatch
         results = self.vv.validate('NM_001424184.1:c.438G>A', 'GRCh38', 'all').format_as_dict(test=True)
         assert 'NM_001424184.1:c.438G>A' in results
@@ -31353,17 +31377,30 @@ def test_issue_801(self):
         assert "NM_014249.4:c.*557del" in results.keys()
         assert "NM_001281446.1:c.*557del" in results.keys()
 
-    def issue_818(self):
+    def test_issue_818(self):
         results = self.vv.validate('NC_000022.10:g.19929250_19929251insCCCCGCC', 'GRCh38', 'mane_select', liftover_level=True).format_as_dict(test=True)
         assert "NM_006440.5:c.70_76dup" in results.keys()
         assert results["NM_006440.5:c.70_76dup"][
             "hgvs_predicted_protein_consequence"] ==  {
-            "lrg_slr": "LRG_417p1:p.V26Gfs*132",
-            "lrg_tlr": "LRG_417p1:p.Val26GlyfsTer132",
-            "slr": "NP_006431.2:p.V26Gfs*132",
-            "tlr": "NP_006431.2:p.Val26GlyfsTer132"
+            "slr": "NP_006431.2:p.(V26Gfs*132)",
+            "tlr": "NP_006431.2:p.(Val26GlyfsTer132)"
         }
 
+    def test_alt_gapping_bug(self):
+        results = self.vv.validate('chr16:2089739:G:C', 'GRCh38', 'mane_select', liftover_level=True).format_as_dict(test=True)
+        assert "NM_001009944.3:c.12900C>G" in results.keys()
+        assert "NT_187607.1:g.705079dup" not in str(results["NM_001009944.3:c.12900C>G"]["alt_genomic_loci"])
+
+    def test_alt_gapping_bug_b(self):
+        results = self.vv.validate('chr16:2089760:C:G', 'GRCh38', 'mane_select', liftover_level=True).format_as_dict(test=True)
+        assert "NM_001009944.3:c.12879G>C" in results.keys()
+        assert "NT_187607.1:g.705077_705079dup" not in str(results["NM_001009944.3:c.12879G>C"]["alt_genomic_loci"])
+
+    def test_alt_gapping_bug_c(self):
+        results = self.vv.validate('chr16:2090285:C:CT', 'GRCh38', 'mane_select', liftover_level=True).format_as_dict(test=True)
+        assert "NM_001009944.3:c.12443dup" in results.keys()
+        assert "NT_187607.1:g.713119_713120insTT" not in str(results["NM_001009944.3:c.12443dup"]["alt_genomic_loci"])
+
 # <LICENSE>
 # Copyright (C) 2016-2026 VariantValidator Contributors
 #