The HEXA NM_000520.6:c.1274_1277dup (NP_000511.2:p.(Tyr427IlefsTer5)) frameshift variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to result in an absent or disrupted protein product. Experimental evidence: Patient-cell and minigene studies showed the mutant HEXA transcript was nearly undetectable and restored to approximately 40% of normal by translation inhibition. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.HEXA encodes the alpha subunit of beta-hexosaminidase, a lysosomal enzyme that helps break down GM2 ganglioside and other molecules containing terminal N-acetyl hexosamines. Harmful changes in HEXA can cause GM2 gangliosidoses, including Tay-Sachs disease, in which GM2 accumulates in nerve cells and leads to progressive neurodegeneration. HEXA is not established as a cancer-related gene.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, very strong: exon-11 c.1274_1277dup causes p.(Tyr427IlefsTer5), a premature truncation before the final exon in a HEXA loss-of-function disease mechanism.
Met, strong: patient-cell and minigene studies showed the mutant HEXA transcript was nearly undetectable and restored to approximately 40% of normal by translation inhibition.
Met: an affected Tay-Sachs patient was compound heterozygous for c.1274_1277dupTATC and the disease-associated c.533G>A (p.R178H) allele.
Met at supporting strength: the exact variant was reported in a patient with confirmed subacute Tay-Sachs disease, a highly specific HEXA-related phenotype.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 (very strong) plus PS3 (strong) satisfy the generic ACMG/AMP Pathogenic rule, with PM3 (moderate) and PP4 (supporting) also applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 868 / 1,613,952 alleles. Recorded AF 0.00053781. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000742443; MAF= 0.07424%, 210/282850 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0129219; MAF= 1.29219%, 134/10370 alleles, homozygotes = 0); grpmax FAF= 0.00033447.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.003. Refer to the recorded PP3/BP4 rationale for interpretation.
35 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 9 not met · 5 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No criterion is assigned because the available literature documents affected individuals or carriers but does not provide the required informative parental, affected-relative, or non-segregation data for PS2, PM6, PP1, or BS4.
PS4 is not met because the reported affected-allele frequency yields an exploratory OR of 2.26 with a 95% CI that includes 1.0, below the ACMG/AMP >5.0 threshold.
PP4 is met at supporting strength from the exact-variant report in a patient with confirmed subacute Tay-Sachs disease.
PP5 and BP6 are not met because there is no exact-variant ClinVar expert-panel benign/pathogenic classification and non-expert submissions are excluded.
BP5 is not met because the second reported allele is another HEXA variant, not an alternate molecular basis.
Both criteria are not_applicable because the variant is a frameshift, outside the generic PP3/BP4 missense and intronic/synonymous/splice-region scope.
The SpliceAI result is not used to assign PP3 or BP4 for this truncating variant.
None of the four requested population criteria is met: grpmax FAF values are below BA1 and BS1 thresholds, no healthy adult homozygote is observed for BS2, and observed all-comers allele frequencies exceed the supplied PM2 threshold.
No criteria match.
PVS1 is met at very strong strength. NM_000520.6:c.1274_1277dup is a four-base duplication causing a frameshift, NP_000511.2:p.(Tyr427IlefsTer5), in exon 11 of the MANE/RefSeq-select HEXA transcript. The predicted premature termination is approximately 100 amino acids before the normal 530-residue terminus and occurs before the final coding exon, supporting loss of the normal protein through nonsense-mediated decay rather than an NMD-escaping terminal truncation. HEXA loss of function is a documented germline disease mechanism in the supplied gene-context assessment. No named downgrade rule is supported: the variant is not an initiation or splice-site exception, is not shown to affect a non-critical distal region, and no evidence indicates that exon 11 is biologically irrelevant or enriched for population loss-of-function variation. The variant and its exon-11 four-base duplication are independently reported in Tay-Sachs disease studies.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PS3 is met at strong strength. Rajavel and Neufeld directly studied the same HEXA founder frameshift, reported as 1278ins4, in patient-derived lymphoblasts and controlled minigene systems. The endogenous mutant transcript was nearly undetectable, increased to approximately 40% of normal after cycloheximide, and was degraded after translation resumed, while normal HEXA mRNA remained stable. The study included normal-cell controls, translation-inhibition and washout controls, nuclear/cytoplasmic fractionation, polysome analysis, and multiple intron-containing and intronless constructs. These reproducible results establish a biologically relevant loss-of-function effect through nonsense-mediated decay for the specified c.1274_1277dup / p.(Tyr427IlefsTer5) allele. Mahuran's review independently places the corresponding four-base insertion in HEXA exon 11 among Tay-Sachs mutations producing a premature stop and summarizes loss of mutant HEXA mRNA in patient cells. The 2006 enzyme-profile study was reviewed but not used as decisive PS3 evidence because the measured enzyme abnormalities were confounded by co-inherited HEXB polymorphisms.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
HEXA-related Tay-Sachs disease is described as recessively inherited. In an affected patient with Tay-Sachs disease, PMID:22441121 reports the target c.1274_1277dupTATC together with c.533G>A (p.R178H), describing the target as the second mutation in patient 23 and documenting the patient as compound heterozygous for these variants. The same paper identifies p.R178H as associated with the B1 phenotype and late-onset Tay-Sachs disease. Compound heterozygosity establishes the target variant in trans with the disease-associated p.R178H allele in an affected proband, supporting PM3.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
PMID:22441121 reports the exact variant in patient 23, who had psychomotor regression, gait abnormalities, and noise hypersensitivity with startle response, and whose diagnosis was confirmed as subacute Tay-Sachs disease. Tay-Sachs disease is a highly specific phenotype for a single genetic etiology involving HEXA, and the reported compound-heterozygous molecular diagnosis is concordant. This supports PP4 at supporting strength.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The relevant literature reports this exact variant in 1 of 34 affected HEXA alleles (2.94%) in an Argentinean Tay-Sachs cohort (PMID:22441121), and the paper reports no exact-variant control comparison. I therefore also performed an exploratory case-versus-matched-ancestry population comparison using the reported case count (1/34) and gnomAD Ashkenazi Jewish controls (391/29,600 alleles; PMID:22441121; gnomad_v4): OR = 2.26, 95% CI 0.31-16.59. The governing PS4 threshold is >5.0 with a confidence interval that does not include 1.0; the explicit comparison is OR 2.26 > 5.0? no, and the CI 0.31-16.59 includes 1.0? yes. Thus PS4 is not met. The literature_pass packet had no ai_classified_papers, and the reviewed variant-specific papers did not provide qualifying case-control enrichment.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is not met under the supplied generic threshold. No governing VCEP specifies a non-cancer or exome-only source, so all-comers gnomAD totals are the default. The variant is observed at AF 0.000742443 in gnomAD v2.1 (210/282850 alleles) and AF 0.00053781 in gnomAD v4.1 (868/1613952 alleles), both above the supplied PM2 supporting threshold of <=0.0001. Although no homozygotes are observed, the allele is present above the applicable threshold and therefore does not satisfy PM2.
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
ClinVar variation 3889 has no expert-panel submissions; its pathogenic classifications are ordinary laboratory or other non-expert assertions. Those assertions cannot trigger PP5 under the required exact-variant expert-panel rule, and the relevant literature is available for independent evaluation rather than being unavailable to the laboratory. Therefore PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. No governing VCEP specifies an alternative population subset, so all-comers gnomAD data are used. The required filtering metric is grpmax FAF, not the Ashkenazi Jewish popmax point estimate: gnomAD v2.1 grpmax FAF is 0.00033447 and gnomAD v4.1 grpmax FAF is 0.00029506, both far below the generic BA1 threshold of 0.05. The Ashkenazi Jewish point estimates of 0.0129219 and 0.0132095 do not establish BA1 because popmax point estimates are not the permitted metric; both population allele counts exceed 2,000.
BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. No governing VCEP specifies a non-cancer or exome-only subset, so all-comers gnomAD data are used. The required filtering metric is grpmax FAF: 0.00033447 in gnomAD v2.1 and 0.00029506 in gnomAD v4.1, both below the generic default BS1 threshold of 0.01. The Ashkenazi Jewish popmax point estimates near 1.3% cannot substitute for FAF. HEXA-related Tay-Sachs disease is autosomal recessive and severe early onset; the conservative qualifying frequency does not establish that this allele frequency is greater than expected for the disorder.
BS1: Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not met. The disorder is autosomal recessive, so the relevant BS2 observation is a healthy adult homozygote. gnomAD v2.1 all-comers reports 0 homozygotes, gnomAD v4.1 all-comers reports 0 homozygotes, gnomAD v2.1 non-cancer exomes reports 0 homozygotes, and gnomAD v3.1 non-cancer genomes reports 0 homozygotes. Heterozygous carrier observations, including the Ashkenazi Jewish enrichment, do not satisfy the recessive genotype requirement, and no case-specific healthy adult homozygote is documented.
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.
The available affected-proband observation is compound heterozygosity for c.1274_1277dupTATC and c.533G>A (p.R178H), supporting a trans relationship in the recessive Tay-Sachs disorder. No observation of the target variant in cis with a pathogenic variant is reported. The trans pathway of BP2 is limited to fully penetrant dominant disorders, which does not apply to this recessive HEXA disorder; therefore BP2 is not met.
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.
The reviewed report describes the patient as carrying a second HEXA variant, c.533G>A, in trans with c.1274_1277dupTATC. This is another molecular alteration in the same disease gene and is not an alternate molecular basis for the disease. No report identifies a different gene or non-HEXA molecular diagnosis explaining the patient's phenotype. BP5 is therefore not met.
Variant found in a case with an alternate molecular basis for disease.
ClinVar variation 3889 contains no exact-variant expert-panel classification as benign or likely benign, and no qualifying reputable benign report was identified. The single Uncertain significance submission and the many pathogenic laboratory submissions do not satisfy BP6. Therefore BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific evidence documents a disease-affected proband with the variant absent from both tested parents, confirmed maternity and paternity, and no family history. PMID:22441121 reports one affected patient with the variant but provides no parental genotype results for that patient; PMID:16352452 reports two brothers carrying the variant as Tay-Sachs carriers, not affected patients. Therefore the evidence does not establish a confirmed de novo event and is insufficient to assess PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No case-specific evidence documents an assumed de novo variant in an affected patient. PMID:22441121 reports one affected patient with the variant but does not report parental testing, and PMID:16352452 concerns two carrier brothers rather than affected patients. The available evidence therefore does not establish an assumed de novo event suitable for PM6.
Assumed de novo, but without confirmation of paternity and maternity.
The available family evidence does not show co-segregation of the variant with disease in multiple affected family members. PMID:16352452 reports two brothers carrying the variant, but both were identified as Tay-Sachs carriers rather than affected individuals. PMID:22441121 reports a single affected patient in a cohort of unrelated families and does not provide segregation results for that patient's relatives. No qualifying affected-family-member meioses are available to assess PP1.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
BS3 was not assessed because the reviewed functional studies do not show that this variant has no damaging effect on HEXA protein function or splicing. The available evidence instead demonstrates degradation of the mutant HEXA transcript and supports loss of function; the enzyme-profile study is not a benign functional assay and is confounded by co-inherited HEXB polymorphisms.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family member is documented to lack the variant in an informative family. PMID:16352452 reports two variant-positive brothers who were carriers, not affected relatives, and PMID:22441121 reports one affected patient without a family non-segregation analysis. Thus, the available evidence does not demonstrate lack of segregation in affected members.
Lack of segregation in affected members of a family.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP3 is not_applicable because its generic computational-evidence scope is limited here to missense variants evaluated with REVEL or intronic, synonymous, or splice-region variants evaluated with SpliceAI. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant, predicted as NP_000511.2:p.(Tyr427IlefsTer5), and therefore lies outside the PP3 scope. The available SpliceAI max delta of 0.003 is not used because a splice prediction cannot establish PP3 for this truncating variant.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP4 is not_applicable because its generic computational-evidence scope is limited here to missense variants evaluated with REVEL or intronic, synonymous, or splice-region variants evaluated with SpliceAI. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant, predicted as NP_000511.2:p.(Tyr427IlefsTer5), and therefore lies outside the BP4 scope. A no-impact SpliceAI result cannot negate the truncating protein effect and is not BP4 evidence for this variant.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in HEXA, mapped onto the exon structure of NM_000520.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish391 / 29,600 | 0.013 |
| Remaining individuals60 / 62,484 | 0.00096 |
| European (Finnish)21 / 64,036 | 0.00033 |
| European (non-Finnish)380 / 1,179,986 | 0.00032 |
| South Asian8 / 91,078 | 8.8e-05 |
| African/African American6 / 74,912 | 8e-05 |
| Admixed American2 / 60,004 | 3.3e-05 |
| Ashkenazi Jewish134 / 10,370 | 0.013 |
| Remaining individuals9 / 7,224 | 0.0012 |
| European (non-Finnish)52 / 129,158 | 0.0004 |
| European (Finnish)6 / 25,124 | 0.00024 |
| African/African American4 / 24,968 | 0.00016 |
| South Asian4 / 30,616 | 0.00013 |
| Admixed American1 / 35,440 | 2.8e-05 |
This variant is present in gnomAD v4.1 (AF= 0.00053781; MAF= 0.05378%, 868/1613952 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0132095; MAF= 1.32095%, 391/29600 alleles, homozygotes = 0); grpmax FAF= 0.00029506.
This variant is present in gnomAD v2.1 (AF= 0.000742443; MAF= 0.07424%, 210/282850 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0129219; MAF= 1.29219%, 134/10370 alleles, homozygotes = 0); grpmax FAF= 0.00033447.
Not available in gnomAD-Canada v1.0.
PP3 is not_applicable because its generic computational-evidence scope is limited here to missense variants evaluated with REVEL or intronic, synonymous, or splice-region variants evaluated with SpliceAI. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant, predicted as NP_000511.2:p.(Tyr427IlefsTer5), and therefore lies outside the PP3 scope. The available SpliceAI max delta of 0.003 is not used because a splice prediction cannot establish PP3 for this truncating variant.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP4 is not_applicable because its generic computational-evidence scope is limited here to missense variants evaluated with REVEL or intronic, synonymous, or splice-region variants evaluated with SpliceAI. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant, predicted as NP_000511.2:p.(Tyr427IlefsTer5), and therefore lies outside the BP4 scope. A no-impact SpliceAI result cannot negate the truncating protein effect and is not BP4 evidence for this variant.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000520.6:c.1274_1277dup in HEXA is a frameshift variant predicted to produce NP_000511.2:p.(Tyr427IlefsTer5). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for HEXA, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. 4 cited in the classification.
The major Ashkenazi Jewish mutation is an example of a frame shift due to a small insertion producing a Stop at codon 431 (Table 4, row 74).
Location Section 7.3, 'Mutations producing premature Stop codons'; Table 4, row 74
Context Review of biochemical, mRNA, transport, and mutation studies of HEXA and related GM2-gangliosidosis genes, including the exon 11 Ashkenazi founder insertion.
The mutant mRNA was nearly undetectable in these cells and increased to approximately 40% of normal in the presence of the translation inhibitor cycloheximide. Stabilized transcript was found in the cytoplasm in association with polysomes. Within 5 h of cycloheximide removal, the polysome-associated nonsense message was completely degraded, while the normal message was stable.
Location Abstract; Results, 'Translation is required for decay of nonsense HEXA mRNA'
Context Normal and Tay-Sachs patient lymphoblasts were compared by Northern blotting, cycloheximide stabilization and washout, subcellular fractionation, and polysome analysis; CHO cells were separately transfected with normal and mutant HEXA minigenes containing varied intron configurations.
Both brothers were found to carry the common exon 11, 1277_1278insTATC mutation, in the HEXA gene.
Location Results, “Identified HEXB polymorphisms in probands”; Table 1
Context Two Ashkenazi Jewish brothers underwent serum and leukocyte hexosaminidase assays and HEXA/HEXB mutation analysis.
The second mutation found in patient 23 was the 4 bp duplication c.1274_1277dupTATC that accounts for 81% of Askenazi Jewish alleles.
Location Results, paragraph discussing patients 21–23; Table 1, patient 23; Discussion, final paragraph; Table 2
Context Molecular analysis of 23 Argentinean patients with Tay-Sachs disease from 17 unrelated families using PCR amplification and sequencing of exonic and flanking intronic HEXA regions.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00053781; MAF= 0.05378%, 868/1613952 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0132095; MAF= 1.32095%, 391/29600 alleles, homozygotes = 0); grpmax FAF= 0.00029506.
This variant is present in gnomAD v2.1 (AF= 0.000742443; MAF= 0.07424%, 210/282850 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0129219; MAF= 1.29219%, 134/10370 alleles, homozygotes = 0); grpmax FAF= 0.00033447.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (35 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 3889)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.