The HEXA NM_000520.6:c.1421+1G>C (NP_000511.2:p.?) splicing variant has not previously been reported in somatic cancers (COSMIC). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Experimental evidence: Patient-fibroblast cDNA studies showed intron 12 retention and abnormal HEXA mRNA for the exact c.1421+1G>C splice variant. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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 at very strong: the canonical +1 splice variant in exon 12 of 14 is predicted to skip 91 coding nucleotides, shifting the reading frame in LOF-sensitive HEXA.
Met at moderate strength: patient-fibroblast cDNA studies showed intron 12 retention and abnormal HEXA mRNA for the exact c.1421+1G>C splice variant.
Met at supporting: SpliceAI max delta 0.00 meets the <=0.1 BP4 threshold for intronic or splice-region variants.
Likely Pathogenic: PVS1 (very strong) plus PS3 (moderate) satisfy the generic ACMG/AMP combination rule; BP4 does not satisfy a benign rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 109 / 1,612,550 alleles. Recorded AF 6.75948e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000115725; MAF= 0.01157%, 29/250594 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00249203; MAF= 0.24920%, 25/10032 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
10 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).
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: 3 met · 8 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No criterion among PS2, PM6, PP1, and BS4 can be assigned from the available evidence because parental testing, family structure, informative meioses, and segregation or non-segregation results are not documented.
Variant-specific patient-fibroblast RNA studies consistently demonstrate abnormal HEXA splice processing, supporting PS3 at moderate strength.
No functional evidence demonstrates preserved splicing or protein function, so BS3 is not met.
No VCEP covers HEXA in this case, so generic ACMG/AMP 2015 rules govern.
The exact variant is documented in affected Tay-Sachs patients, but the available literature does not provide PS4 case-control data, current-patient phenotype data for PP4, an alternate molecular basis for BP5, or a qualifying ClinVar expert-panel assertion for PP5/BP6.
The variant is an intronic canonical splice-site change, so PP3 and BP4 were adjudicated only through SpliceAI; REVEL and BayesDel were not used.
SpliceAI max delta 0.00 does not meet PP3 >= 0.2 but meets BP4 <= 0.1 at supporting strength.
Population evidence supports none of the four requested criteria: the variant is rare, has no observed homozygotes, is far below BA1/BS1 frequency thresholds, and narrowly exceeds the explicit PM2 threshold in gnomAD v2.1 despite qualifying in gnomAD v4.1.
No criteria match.
PVS1 is met at very strong strength. NM_000520.6:c.1421+1G>C is a canonical donor-site (+1) splice variant in the MANE Select transcript NM_000520.6, satisfying the ACMG/AMP null-variant definition. HEXA loss of function is supported as a germline disease mechanism in the gene-level assessment. The affected exon is exon 12 of 14, is neither the first, penultimate, nor last exon, and contains 91 coding nucleotides; exon skipping would remove 91 nucleotides (91 % 3 = 1) and shift the reading frame, predicting a premature truncating consequence rather than an in-frame change. The exact variant has been shown to produce abnormal HEXA mRNAs with retained or truncated intron 12, and the extracted finding describes the abnormal transcripts as unstable, supporting loss of transcript function. No named downgrade rule is triggered: the transcript is clinically relevant, the affected exon is internal rather than a non-critical distal terminal exon, and the predicted consequence does not escape the expected NMD-sensitive region. No repeat-region context or population LoF-enrichment evidence is present in the supplied case evidence. The ClinGen SVI generic PVS1 framework is therefore applied without downgrade.
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 moderate strength. PMID:2837213 directly evaluated the exact HEXA splice-site change corresponding to NM_000520.6:c.1421+1G>C using cDNA cloning and sequencing from patient fibroblasts, with genomic hybridization controls across multiple patient cell lines. The study found retention of intact or truncated intron 12 in abnormal HEXA mRNAs and documented the donor-site G-to-C substitution; its direct result states, "However, the first nucleotide at the 5' donor site of intron 12 was consistently C, instead of the normal G." PMID:2973464 independently reports cDNA analysis from fibroblasts showing abnormal clones with intron 12 retention for the same G-to-C donor-site mutation. These concordant variant-specific RNA studies demonstrate abnormal splicing and support a damaging effect on the HEXA gene product. The evidence does not justify strong strength because the available material does not establish validated clinical-laboratory reproducibility or a fully quantified assay calibration.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
NM_000520.6:c.1421+1G>C is an intronic canonical donor-site variant, so the governing generic rule selects the SpliceAI path only; REVEL and BayesDel are not applicable to BP4 in this situation. SpliceAI maximum delta is 0.00, meeting the generic BP4 supporting threshold of <= 0.1 from the supplied Jaganathan et al. 2019 calibration (PMID:30661751). BP4 is therefore met at supporting strength.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
PM2 is not met under the supplied generic threshold. The variant is present in both default all-comers datasets: gnomAD v2.1 total AF is 0.000115725 (29/250594), which is above the recessive PM2 threshold of 0.0001, while gnomAD v4.1 total AF is 6.75948e-05 (109/1612550), which is below it. The newer v4.1 value alone would qualify as extremely low frequency, but the v2.1 value exceeds the explicit threshold; therefore the combined population evidence does not satisfy PM2 consistently.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868) ... PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
NM_000520.6:c.1421+1G>C is an intronic canonical donor-site variant, so the governing generic rule selects the SpliceAI path only; REVEL and BayesDel are not applicable to PP3 in this situation. SpliceAI maximum delta is 0.00, below the generic PP3 supporting threshold of >= 0.2 and moderate threshold of >= 0.5, using the supplied Jaganathan et al. 2019 calibration (PMID:30661751). PP3 is therefore not met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
ClinVar reports Pathogenic for the exact variant, but the record has no expert-panel classification and is labeled criteria provided, multiple submitters, no conflicts, with clinical-laboratory submissions. Under the required generic rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions do not trigger PP5; therefore this evidence does not meet PP5.
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. The relevant filtering allele-frequency measure is the gnomAD grpmax FAF, not the Ashkenazi Jewish popmax point estimate: gnomAD v2.1 reports grpmax FAF 7.03e-06 and gnomAD v4.1 reports grpmax FAF 2.47e-06, both below the generic BA1 stand-alone threshold of 0.05. The Ashkenazi Jewish observed frequencies (25/10032 alleles in v2.1 and 89/29568 in v4.1) are not substituted for grpmax FAF; both populations have more than 2000 observed alleles, but neither filtering FAF supports BA1.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868) ... BA1: Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. Using the required filtering allele-frequency measure, gnomAD v2.1 grpmax FAF is 7.03e-06 and gnomAD v4.1 grpmax FAF is 2.47e-06, both far below the generic 0.01 default. The variant is observed at low frequency in the Ashkenazi Jewish population, but the point estimates are not used for this decision. These data do not show an allele frequency greater than expected for the rare autosomal-recessive Tay-Sachs disorder; a maximum-credible-frequency calculation is not necessary to reject BS1 because both filtering FAF values are already well below the default threshold.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168) ... BS1: Allele frequency is greater than expected for the disorder.
BS2 is not met. gnomAD v2.1 reports zero homozygotes among 250594 alleles and gnomAD v4.1 reports zero homozygotes among 1612550 alleles. No healthy adult homozygote for this recessive disorder is documented in the supplied population data, so the required observation supporting BS2 is absent.
BS2: 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.
BS3 is not met. The available functional studies evaluate the exact variant and report abnormal HEXA RNA processing with intron 12 retention; they do not show no damaging effect on protein function or splicing. No benign functional assay result was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No qualifying benign or likely benign exact-variant ClinVar expert-panel classification is present. ClinVar instead reports Pathogenic from clinical-laboratory submissions without an expert panel, and the reviewed literature contains no reputable benign assertion that meets the specified PP5/BP6 restriction; 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.
The available report describes the variant in affected Tay-Sachs patients, including compound heterozygous patients, but provides no maternity confirmation, paternity confirmation, parental genotypes, or explicit de novo determination. Therefore the PS2 requirements cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No reviewed source provides a case-control comparison for the exact NM_000520.6:c.1421+1G>C variant. PMID:2837213 reports the variant in affected Ashkenazi Jewish Tay-Sachs patients, but it is a functional/case report without unaffected or population control counts; therefore an OR and 95% CI cannot be computed. The governing ACMG/AMP threshold is not reached because the required comparative estimate is unavailable.
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.
HEXA-related Tay-Sachs disease is recessive, and PMID:2837213 reports the exact donor-site variant in affected patients GM0502B and GM2968 as compound heterozygous with a normal sequence on the other allele. However, the available evidence does not identify a pathogenic variant in trans, and it does not establish parental testing or phase with a pathogenic allele as required for PM3. The report therefore cannot support application of PM3, but the criterion is not assessed rather than called absent because the pathogenicity of any second allele is not fully documented in the available evidence.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The available report documents the variant in affected patients but does not state that it was assumed de novo and does not provide parental testing or inheritance information. The PM6 requirement therefore cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The available report includes more than one affected patient with the variant, but it does not establish that they are affected members of the same family, does not provide family pedigrees or informative meioses, and does not report variant co-segregation with disease. PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The reviewed literature describes infantile Tay-Sachs disease in patients carrying the exact variant, including the classical infantile phenotype in PMID:2837213. However, the case materials do not provide the phenotype or family history of the individual being adjudicated, so the requirement concerning the patient's phenotype cannot be evaluated for this case.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No affected family members with documented absence of the variant are reported, and no pedigree or non-segregation analysis is available. The evidence does not establish lack of segregation and is insufficient to assess BS4.
Lack of segregation in affected members of a family.
No available case evidence documents this variant in cis with a pathogenic variant, or in trans with a pathogenic variant in a fully penetrant dominant gene or disorder. The affected HEXA reports concern a recessive disorder and do not establish a qualifying BP2 allelic observation; therefore BP2 is not assessed.
BP2: 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.
No reviewed evidence shows that this variant was found in a case with an alternate molecular basis for disease. The literature reports Tay-Sachs patients carrying the variant and functional splice effects, but does not establish an alternate molecular cause for the disease in the adjudicated case.
Variant found in a case with an alternate molecular basis for disease.
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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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
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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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
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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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 Jewish89 / 29,568 | 0.003 |
| Remaining individuals13 / 62,420 | 0.00021 |
| European (non-Finnish)7 / 1,178,898 | 5.9e-06 |
| Ashkenazi Jewish25 / 10,032 | 0.0025 |
| Remaining individuals1 / 6,120 | 0.00016 |
| European (non-Finnish)3 / 113,462 | 2.6e-05 |
This variant is present in gnomAD v4.1 (AF= 6.75948e-05; MAF= 0.00676%, 109/1612550 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00301001; MAF= 0.30100%, 89/29568 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
This variant is present in gnomAD v2.1 (AF= 0.000115725; MAF= 0.01157%, 29/250594 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00249203; MAF= 0.24920%, 25/10032 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Not available in gnomAD-Canada v1.0.
NM_000520.6:c.1421+1G>C is an intronic canonical donor-site variant, so the governing generic rule selects the SpliceAI path only; REVEL and BayesDel are not applicable to BP4 in this situation. SpliceAI maximum delta is 0.00, meeting the generic BP4 supporting threshold of <= 0.1 from the supplied Jaganathan et al. 2019 calibration (PMID:30661751). BP4 is therefore met at supporting strength.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
NM_000520.6:c.1421+1G>C is an intronic canonical donor-site variant, so the governing generic rule selects the SpliceAI path only; REVEL and BayesDel are not applicable to PP3 in this situation. SpliceAI maximum delta is 0.00, below the generic PP3 supporting threshold of >= 0.2 and moderate threshold of >= 0.5, using the supplied Jaganathan et al. 2019 calibration (PMID:30661751). PP3 is therefore not met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.2 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
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.1421+1G>C in HEXA is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000511.2:p.?. 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). REVEL score = 0.928. BayesDel score = 0.66.
5 paper records listed. 2 cited in the classification.
However, the first nucleotide at the 5' donor site of intron 12 was consistently C, instead of the normal G.
Location Results, “Structure of cDNAs,” p. 466; “Genomic DNA Analysis for the Junctional Transversion,” pp. 466–467
Context HEXA cDNA cloning and Sanger sequencing from fibroblasts of patient cell line GM0502B; genomic DNA hybridization with normal and mutant 21-mer oligonucleotide probes in GM0502B, GM2968, and GM0515A.
We showed previously that three of these mRNAs retained intron 12 with a mutation from G to C at the 5' donor site
Location Abstract
Context cDNA clone isolation and sequencing from fibroblasts of a compound-heterozygous Ashkenazi Jewish patient with Tay-Sachs disease.
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= 6.75948e-05; MAF= 0.00676%, 109/1612550 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00301001; MAF= 0.30100%, 89/29568 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
This variant is present in gnomAD v2.1 (AF= 0.000115725; MAF= 0.01157%, 29/250594 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00249203; MAF= 0.24920%, 25/10032 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories). (ClinVarID = 3890)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.928. BayesDel score = 0.66.
This variant has not previously been reported in somatic cancers (COSMIC).