The SOD1 NM_000454.5:c.14C>T (NP_000445.1:p.(Ala5Val)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Independent A4V assays showed at least 18-fold faster dimer dissociation than wild-type SOD1 and reproducible structural, stability, and aggregation abnormalities. 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.SOD1 produces a copper- and zinc-containing antioxidant enzyme that helps protect cells by converting harmful superoxide molecules into oxygen and hydrogen peroxide. Changes in this gene can cause familial amyotrophic lateral sclerosis (ALS), a progressive disease affecting nerve cells that control movement. SOD1 has no established direct role in cancer.
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: The same Ala-to-Val substitution is reported as pathogenic SOD1 A4V in multiple ALS studies, despite the one-residue mature-protein numbering offset.
Met at moderate strength: independent A4V assays showed at least 18-fold faster dimer dissociation than wild-type SOD1 and reproducible structural, stability, and aggregation abnormalities.
Met at supporting: gnomAD v4.1 grpmax FAF is 2.8e-07, below the <=0.0001 PM2 threshold, with zero homozygotes.
Met at moderate strength: missense REVEL 0.853 meets the >=0.773 PP3 threshold.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 (strong), PS3 (moderate), PM2 (supporting), and PP3 (moderate) satisfy the generic ACMG/AMP fallback rule of 1 strong plus 1–2 moderate criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,613,934 alleles. Recorded AF 1.23921e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.5929e-05; MAF= 0.00359%, 9/250494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.95672e-05; MAF= 0.00796%, 9/113112 alleles, homozygotes = 0); grpmax FAF= 4.135e-05.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.853. Refer to the recorded PP3/BP4 rationale for interpretation.
8 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 · 10 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The functional evidence supports PS3 at moderate strength because multiple independent variant-specific assays with wild-type or assay controls consistently demonstrate damaging SOD1 biophysical phenotypes, while the supplied record does not establish clinical-laboratory validation required for strong strength.
BS3 is not met because no study demonstrates preserved SOD1 protein function or normal splicing for this variant.
PS4 was not assessed because the only verified case-control result was for a linked haplotype, not exact-variant carrier prevalence with an OR/RR and 95% CI.
PP4 was not met because ALS is not highly specific for a single genetic etiology.
PP5 and BP6 were not met because no exact-variant ClinVar expert-panel assertion exists and published evidence is independently available.
BP5 was not assessed because no alternate molecular basis was documented.
For this missense variant, the generic computational-evidence path is REVEL only: PP3 is met at moderate strength by REVEL 0.853, while BP4 is not met because the score exceeds the <=0.29 benign threshold.
No criteria match.
NM_000454.5:c.14C>T produces NP_000445.1:p.(Ala5Val). Multiple studies report the same alanine-to-valine substitution as SOD1 A4V under mature-protein numbering and describe it as pathogenic in ALS. The one-residue numbering difference is an annotation convention; the amino-acid change is identical.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PS3 is met at moderate strength. The queried SOD1 c.14C>T, p.(Ala5Val) variant is the A4V mature-protein variant studied in multiple independent functional systems. Recombinant human A4V showed accelerated unfolding, zinc and copper release, beta-barrel conformational change, and dimer dissociation, with dimer dissociation at least 18-fold faster than wild type (PMID:21549128). Independent structural and biophysical analyses found disordered metal-binding-loop regions, concentration-dependent self-association/monomerization, and marked thermal destabilization of A4V (PMID:19800308). In HEK293FT cells, A4V was evaluated against wild type and used as a normalized aggregation control; the aggregation assay was repeated at least three times and up to 24 times for wild type and A4V controls (PMID:19483195). These variant-specific results consistently support impaired SOD1 stability, folding, and aggregation-related function, but the supplied evidence does not establish validation and reproducibility in a clinical diagnostic laboratory setting or a single directly disease-proximal assay sufficient for strong strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 is met at supporting strength. The variant is present but extremely rare in the default all-comers populations: gnomAD v4.1 has AF=1.23921e-06 with grpmax FAF=2.8e-07, and gnomAD v2.1 has AF=3.5929e-05 with grpmax FAF=4.135e-05. The gnomAD v2.1 non-cancer-exome result is concordant (AF=3.80418e-05; grpmax FAF=4.516e-05), and all sources report zero homozygotes; these values are <= the supplied PM2 supporting threshold of 0.0001.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, NM_000454.5:c.14C>T (p.Ala5Val), so the governing generic rule requires the missense REVEL path only; SpliceAI and BayesDel are not used. REVEL is 0.853, meeting the generic PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The SOD1 VCEP record has no released criterion specifications and vcep_materials.json has no SOD1 domain-table entry to establish an authoritative critical domain. The variant is also reported as absent from the statistically significant cancer-hotspot search. The supplied SOD1 literature describes ALS-associated point mutations as scattered throughout the protein and provides no evidence that residue 5 is a mutational hotspot or a critical, well-established functional domain without benign variation.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The verified literature describes the variant in patients with amyotrophic lateral sclerosis, including rapidly progressive lower-motor-neuron disease. That phenotype is not highly specific for a single genetic etiology because ALS is genetically heterogeneous and can occur through multiple molecular causes; the case materials provide no phenotype or family-history evidence that makes this presentation uniquely diagnostic of SOD1-related disease. Thus the generic PP4 definition is not satisfied.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The exact variant is classified as Pathogenic in ClinVar by ordinary clinical-laboratory submissions, with zero expert-panel submissions. The verified PMID:19176896 paper reports A4V as causing a rapidly progressive dominant ALS phenotype, but its clinical and genetic findings are available for independent evaluation and therefore do not satisfy the PP5 condition that the evidence be unavailable to the laboratory. Ordinary submissions, aggregate ClinVar labels, and non-expert assertions cannot independently trigger PP5 under the required exact-variant expert-panel rule.
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 governing generic threshold is >=0.05, but the appropriate filtering frequency is gnomAD v4.1 grpmax FAF=2.8e-07; gnomAD v2.1 all-comers grpmax FAF=4.135e-05 and non-cancer exomes grpmax FAF=4.516e-05 are also far below 0.05. The observed gnomAD population has 2/1,613,934 total alleles in v4.1 and no homozygotes, so no population-frequency basis supports a stand-alone benign call.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the available population data. The generic default threshold is >=0.01, whereas the filtering gnomAD v4.1 grpmax FAF is 2.8e-07; gnomAD v2.1 all-comers and non-cancer-exome grpmax FAF values are 4.135e-05 and 4.516e-05, respectively. These are not greater than expected for a rare SOD1 ALS disorder, and no prevalence, penetrance, or allelic-heterogeneity calculation is needed to convert these much lower frequencies into BS1.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The available variant-specific functional studies report destabilization, accelerated unfolding, impaired dimer behavior, structural disorder, and aggregation-related abnormalities for A4V rather than demonstrating no damaging effect on SOD1 protein function or splicing. No well-established benign functional assay result with appropriate controls was identified for this variant.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
SOD1 disease evidence does not support a gene in which primarily truncating variants cause disease. The supplied literature instead describes numerous disease-associated point or missense mutations and a gain-of-function mechanism, while the queried variant is missense.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot substitute for REVEL, and BayesDel has no established generic calibration. REVEL is 0.853, which does not meet any BP4 threshold, including the supporting threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The exact variant has no ClinVar expert-panel benign or likely-benign classification. ClinVar instead shows Pathogenic clinical-laboratory submissions, and the supplied literature reports A4V in association with ALS. Because ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6, the required reputable-source benign assertion is absent.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The available evidence identifies SOD1 c.14C>T (p.Ala5Val, also reported as mature-protein A4V) in ALS cohorts and families, but does not document a specific proband with confirmed maternity and paternity, parental variant testing, or absence of family history. Therefore, the required de novo evidence for PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The literature_pass.json ai_classified_papers lead PMID:19176896 was verified against the full text. It studied the exact Ala-to-Val SOD1 substitution as mature-protein A4V, corresponding to NM_000454.5:c.14C>T / NP_000445.1:p.(A5V), and included 54 North American A4V patients and control groups. However, the paper's case-control analysis compared a linked 10-polymorphism haplotype, reporting haplotype frequency 0.23 in cases versus 0.0 in controls and p = 3.0e-11, not the c.14C>T variant itself. The paper does not provide variant-carrier counts in affected individuals and controls, nor a variant-specific OR/RR and 95% CI. Therefore a variant-specific case-control OR cannot be computed from the reported data; the haplotype association was not substituted for a variant OR. The governing PS4 comparison is >5.0 with a confidence interval that does not include 1.0, but no variant-specific estimate is available, so the required inequality cannot be evaluated (OR > 5.0? not assessable; 95% CI excludes 1.0? not assessable).
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: 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.
The supplied evidence establishes the same Ala-to-Val change as A4V, which supports PS1, but does not identify a different missense substitution at the same SOD1 residue 5 that was determined to be pathogenic. The available PM5 candidate artifact contains no comparator candidates, and no reliable same-residue alternative was found in the supplied evidence.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The available evidence does not document an assumed de novo SOD1 c.14C>T (p.Ala5Val) occurrence in a specific affected patient. The cohort and functional reports do not provide a proband-level de novo observation or parental testing information; therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
The evidence establishes that SOD1 A4V/p.Ala5Val occurs in familial ALS cohorts, including 54 North American A4V families, but does not provide genotype and disease-status data for multiple affected relatives, a count of informative meioses, or variant-specific segregation results. The available evidence is insufficient to apply PP1 or determine a stronger segregation level.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The evidence supports that SOD1 disease is commonly associated with missense or point mutations, including more than 100 or 146 reported disease-associated mutations, but it does not provide a gene-wide analysis demonstrating a low rate of benign missense variation. Both required PP2 components are therefore not established from the supplied evidence.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
BS2 cannot be assessed from the available evidence. gnomAD reports zero homozygotes for this variant, but the nine v2.1 and two v4.1 heterozygous observations do not establish that the carriers were healthy adults, their ages, or their penetrance status. No documented healthy adult heterozygote or qualifying early-onset full-penetrance context is available for this criterion.
BS2
No affected family member is documented to lack SOD1 c.14C>T (p.Ala5Val), and no family-level non-segregation analysis is reported. The available literature does not provide the affected-member genotypes and phenotype information needed to distinguish true lack of segregation from phenocopy or another pathogenic variant; therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family.
BP2 requires either observation of the variant in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant in any inheritance pattern. The available evidence supports a dominant SOD1 ALS context, but it does not identify a second pathogenic variant in the same individual and does not establish cis or trans phase through parental, offspring, or other validated phasing data. Consequently, BP2 cannot be met or excluded from the available case evidence and is not assessed.
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 case-level evidence in the supplied materials documents an alternate molecular basis for the patient's disease, such as a second pathogenic variant or another established molecular diagnosis. The BP5 rule requires that the variant be found in a case with such an alternate basis; without case-level alternate-basis data, the criterion cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000454.5:c.14C>T in SOD1 is a missense substitution predicted to produce NP_000445.1:p.(Ala5Val). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for SOD1, 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_null_variant_class
PM3 is limited to recessive disorders and requires the tested variant to be detected in trans with a pathogenic variant, with phase established through parental or offspring testing. The available SOD1 evidence describes the queried A4V/A5V variant in autosomal-dominant ALS, not a recessive disorder, and provides no basis for applying a recessive allelic criterion. Therefore PM3 is not applicable under the generic ACMG/AMP definition.
For recessive disorders, detected in trans with a pathogenic variant
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_000454.5:c.14C>T in SOD1 is a missense substitution predicted to produce NP_000445.1:p.(Ala5Val). 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 SOD1, 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
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000454.5:c.14C>T in SOD1 is a missense substitution predicted to produce NP_000445.1:p.(Ala5Val). 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 SOD1, 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_000454.5:c.14C>T in SOD1 is a missense substitution predicted to produce NP_000445.1:p.(Ala5Val). 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 SOD1, 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 SOD1, mapped onto the exon structure of NM_000454.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)2 / 1,179,914 | 1.7e-06 |
| European (non-Finnish)9 / 113,112 | 8e-05 |
This variant is present in gnomAD v4.1 (AF= 1.23921e-06; MAF= 0.00012%, 2/1613934 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69504e-06; MAF= 0.00017%, 2/1179914 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.5929e-05; MAF= 0.00359%, 9/250494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.95672e-05; MAF= 0.00796%, 9/113112 alleles, homozygotes = 0); grpmax FAF= 4.135e-05.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_000454.5:c.14C>T (p.Ala5Val), so the governing generic rule requires the missense REVEL path only; SpliceAI and BayesDel are not used. REVEL is 0.853, meeting the generic PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot substitute for REVEL, and BayesDel has no established generic calibration. REVEL is 0.853, which does not meet any BP4 threshold, including the supporting threshold of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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_000454.5:c.14C>T in SOD1 is a missense substitution predicted to produce NP_000445.1:p.(Ala5Val). 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 SOD1, 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 = 0.14). REVEL score = 0.853. BayesDel score = 0.419668.
8 paper records listed. 4 cited in the classification.
One of these, alanine to valine substitution on codon 4 (A4V; GCC¡GTC) in exon 1
Location Introduction, paragraph 2; Abstract; Results and Discussion sections
Context Case-control and haplotype association study involving 54 North American patients with confirmed A4V mutation, 3 Swedish and 6 Italian A4V patients, non-A4V SOD1 mutation patients, sporadic ALS patients, and population controls.
To date, 146 different mutations in superoxide dismutase 1 (SOD1) have been identified in patients with familial amyotrophic lateral sclerosis (ALS).
Location Abstract
Context Cell-based aggregation assay using transient expression of wild-type and mutant SOD1 in HEK293FT cells.
The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS.
Location Abstract; Results, ‘Structures of metal-free A4V and G93A SOD1’
Context Recombinant human A4V SOD1 was analyzed by X-ray crystallography, analytical ultracentrifugation, and differential scanning calorimetry-related biophysical analysis.
The A4V mutation, which is the most common SOD1-associated mutation in North America,2 introduces a bulky amino acid that destabilizes the dimer interface.49
Location Introduction, paragraph describing the five mutations; Results and Discussion, ‘ALS-causing mutations accelerate all steps in the SOD1 unfolding pathway’
Context In vitro time-resolved unfolding assays of recombinant human SOD1 expressed on a wild-type background, measuring metal release, beta-barrel conformational change, and dimer dissociation.
More than 100 point mutations of the superoxide scavenger Cu/Zn superoxide dismutase (SOD; EC ) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism.
Abstract
Mutations at dozens of sites in SOD1 induce amyotrophic lateral sclerosis (ALS), a fatal gain-of-function neurodegenerative disease whose molecular basis is unknown.
Abstract
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= 1.23921e-06; MAF= 0.00012%, 2/1613934 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69504e-06; MAF= 0.00017%, 2/1179914 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.5929e-05; MAF= 0.00359%, 9/250494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.95672e-05; MAF= 0.00796%, 9/113112 alleles, homozygotes = 0); grpmax FAF= 4.135e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories). (ClinVarID = 14763)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.853. BayesDel score = 0.419668.
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.