The IDH1 NM_005896.4:c.395G>A (NP_005887.2:p.(Arg132His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61615239, n = 5513 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Independent biochemical, cellular, and mouse studies show IDH1 R132H neomorphic activity, including approximately tenfold increased serum 2-hydroxyglutarate and impaired differentiation. 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.IDH1 encodes a cytoplasmic and peroxisomal enzyme that converts isocitrate to alpha-ketoglutarate and helps produce NADPH, supporting cellular metabolism and antioxidant processes. Altered IDH1 activity is associated with several cancers, including glioma, cholangiocarcinoma, and acute myeloid leukemia. In cancer, abnormal IDH1 activity can produce D-2-hydroxyglutarate, which disrupts cellular enzymes that regulate DNA and histone modification and can promote tumor development.
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: Independent biochemical, cellular, and mouse studies show IDH1 R132H neomorphic activity, including approximately tenfold increased serum 2-hydroxyglutarate and impaired differentiation.
Met: Arg132 is a statistically significant IDH1 hotspot and active-site gate-keeper residue, while gnomAD v4.1 frequency is 16/1,613,530 alleles.
Met at supporting strength: gnomAD v4.1 AF 9.91615e-06 is below the <=0.0001 PM2 threshold, with zero homozygotes.
Met: R132C, R132L, and R132S are recurrent same-residue IDH1 substitutions in human gliomas with the same gain-of-function activity.
Met at moderate strength: missense REVEL score 0.852 exceeds the PP3 moderate threshold of 0.773.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong plus PM1 and PM5 moderate, PP3 moderate, and PM2 supporting satisfy the generic ACMG/AMP 2015 combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 16 / 1,613,530 alleles. Recorded AF 9.91615e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.852. Refer to the recorded PP3/BP4 rationale for interpretation.
8 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61615239, n = 5513 times).
This variant lies 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: 5 met · 6 not met · 13 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The codon/residue evidence supports PM1 because Arg132 is an IDH1 active-site hotspot and supports PM5 because other Arg132 missense substitutions are recurrent and functionally altered.
PS1, PP2, and BP1 remain not assessed because the supplied evidence lacks the specific alternate-nucleotide, gene-wide benign-missense, and truncating-spectrum evidence required by their generic definitions.
PS3 is met at strong strength because independent, variant-specific biochemical, cellular, and in-vivo studies consistently demonstrate damaging neomorphic IDH1 R132H effects.
BS3 is not met because no reviewed assay demonstrates preserved protein function or normal splicing for this variant.
No VCEP covers IDH1 in this case, so generic ACMG/AMP rules govern.
PS4 lacks the required exact-variant case-control RR/OR and confidence interval; PP4 lacks case-specific phenotype or family-history specificity; BP5 lacks a case-level alternate molecular basis.
PP5 and BP6 are not triggered because the exact-variant ClinVar record has zero expert-panel submissions and does not provide a qualifying expert-panel classification.
Neither PM3 nor BP2 is assessed because the supplied evidence lacks a phase-resolved second pathogenic variant observation.
The available papers describe somatic IDH1 R132H biology and do not establish allelic ACMG/AMP evidence for this target variant.
No criteria match.
PS3 is met at strong strength. Multiple independent, variant-specific functional studies evaluated IDH1 p.Arg132His with appropriate wild-type or control comparisons and complementary systems. Purified-enzyme and cellular assays showed loss of native isocitrate-dependent activity together with neomorphic NADPH-dependent alpha-ketoglutarate reduction and production of R-2-hydroxyglutarate (PMID:19935646). Independent glioma-cell and xenograft experiments demonstrated altered enzymatic activity, increased D-2-hydroxyglutarate, reduced proliferation, and an in-vivo phenotype (PMID:21446021). Conditional knock-in mouse studies showed approximately tenfold increased serum 2-hydroxyglutarate, progenitor expansion, splenomegaly, anemia, extramedullary hematopoiesis, and epigenetic abnormalities (PMID:22763442). Human erythroleukemia and murine progenitor-cell models reproduced increased 2-hydroxyglutarate, cytokine-independent growth, and impaired differentiation, with rescue when the metabolite pathway was reduced (PMID:23393090). Isogenic human astrocyte experiments additionally showed mutant-specific 2-hydroxyglutarate production and reproducible methylome remodeling (PMID:22343889). These orthogonal biochemical, cellular, and in-vivo results directly support a damaging neomorphic effect of the exact R132H variant; no generic numeric strength threshold was supplied beyond the governing ACMG/AMP definition, so the original PS3 strong category is retained rather than upgraded.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
p.Arg132His lies at IDH1 Arg132, a recurrent statistically significant hotspot, and PMID:19935646 describes Arg132 as a gate-keeper residue in the active site and reports altered enzymatic activity for the R132H substitution. The case has no VCEP domain table for IDH1; the available population data show the variant is extremely rare in gnomAD v4.1 (16/1,613,530 alleles; AF 9.91615e-06; no homozygotes), with no benign classification or common benign variation presented for this hotspot.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is met at supporting strength. The generic SVI threshold supplied for PM2 is <=0.0001, and the variant's all-comers gnomAD v4.1 AF is 9.91615e-06 (16/1,613,530 alleles; 0 homozygotes), while gnomAD v2.1 exomes reports AF=0 (0/251,268 alleles; 0 homozygotes). These population frequencies are below the PM2 supporting threshold. No VCEP-specific population source governs this case, so the all-comers entries are the applicable defaults.
PM2 (supporting): <= 0.0001
PMID:19935646 reports other missense substitutions at the same Arg132 residue—R132C, R132L, and R132S—in human gliomas and states that each produced the same gain-of-function NADPH-dependent reduction of alpha-ketoglutarate observed for R132H. These established recurrent disease-associated same-residue substitutions support PM5 for p.Arg132His, although the paper does not provide separate ClinVar-style pathogenic classifications for each comparator.
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.
Scope was settled first: NM_005896.4:c.395G>A is a missense variant producing NP_005887.2:p.(Arg132His), so the generic PP3/BP4 missense path uses REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.852, which meets the supplied generic PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. Therefore PP3 is met at moderate strength. The calibrated threshold is from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
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)
ClinVar contains exact-variant pathogenic and likely pathogenic submissions, but the record reports zero expert-panel submissions and only single-submitter or otherwise non-expert assertions. Under the required PP5 guardrail, these assertions cannot trigger 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. Under the generic stand-alone threshold of >=0.05, the highest observed all-comers frequency is 9.91615e-06 in gnomAD v4.1 (16/1,613,530 alleles; 0 homozygotes), and gnomAD v2.1 exomes reports 0/251,268 alleles. These frequencies are far below 0.05. No VCEP-specific population source governs this case, so the all-comers gnomAD entries are the applicable defaults.
BA1 (stand-alone): >= 0.05
BS1 is not met under the supplied generic default threshold of >=0.01. The all-comers gnomAD v4.1 AF is 9.91615e-06, with a maximum reported subpopulation AF of 3.37769e-05, and gnomAD v2.1 exomes reports AF=0; all are below 0.01. No disorder-specific prevalence, penetrance, or VCEP-derived threshold is available to support a lower gene-specific BS1 threshold.
BS1 (strong): >= 0.01
BS3 is not met. The available variant-specific functional studies do not show no damaging effect on protein function or splicing; instead, they consistently report altered IDH1 enzymatic activity, 2-hydroxyglutarate production, cellular phenotypes, epigenetic remodeling, or in-vivo effects. No well-established benign functional assay with adequate controls was identified for IDH1 p.Arg132His.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Scope was settled first: NM_005896.4:c.395G>A is a missense variant producing NP_005887.2:p.(Arg132His), so the generic BP4 missense path uses REVEL only; the SpliceAI result cannot substitute for a gray-zone or non-supportive REVEL result. The REVEL score is 0.852, which does not meet any supplied generic BP4 threshold (supporting <= 0.29, moderate <= 0.183, or strong <= 0.016). Therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
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)
ClinVar has no exact-variant expert-panel benign or likely benign classification; it contains pathogenic and likely pathogenic submissions and reports zero expert-panel submissions. Ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6 under the required guardrail.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is p.Arg132His, but the available evidence does not document a previously established pathogenic variant produced by a different nucleotide change that causes the same amino-acid substitution. The exact c.395G>A variant itself cannot establish the required alternate-nucleotide comparison.
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.
The available record identifies one ClinVar submission as having origin "de novo", but provides no proband-level clinical report, family-history information, or molecular confirmation that both maternity and paternity were confirmed. Therefore the complete PS2 definition cannot be established from the available evidence.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No case-control study result for the exact variant was available with a relative risk or odds ratio and its confidence interval. The governing ACMG/AMP note requires an RR or OR >5.0 with a confidence interval that does not include 1.0; therefore PS4 cannot be assessed from the available case observations or population data.
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 PM3 requirement cannot be assessed from the available evidence. No affected-proband observation documents NM_005896.4:c.395G>A in trans with a pathogenic variant, and no parental or offspring testing establishes phase. The available case information does not establish a recessive disorder context for this target observation.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
A ClinVar submission records the variant origin as "de novo", but the available evidence does not document the underlying case, the patient's disease phenotype, or how the de novo assumption was established. The record therefore cannot support PM6 as a clinical evidence assertion.
Assumed de novo, but without confirmation of paternity and maternity.
No affected relatives, informative meioses, genotype results in family members, or phenotype-segregation observations are documented. The available variant reports are isolated records and do not establish co-segregation with disease in multiple affected family members.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The supplied evidence does not provide a gene-wide assessment demonstrating both a low rate of benign missense variation in IDH1 and that missense variants are a common disease mechanism under the generic PP2 definition. Variant-level rarity and recurrent cancer hotspot evidence cannot substitute for those gene-level requirements.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The case materials do not provide a patient phenotype or family history sufficiently specific for a disease with a single genetic etiology. Variant-associated cancer and disease labels in databases are not a substitute for the patient's phenotype or family history required by PP4.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. The gnomAD records show zero homozygotes, but do not document an observed healthy adult individual carrying this variant, and the case does not establish a fully penetrant early-onset inherited disorder or the relevant inheritance model. Therefore the required BS2 observation is not available.
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.
No family pedigree or testing results identify affected relatives who lack the variant. Consequently, lack of segregation cannot be evaluated, and there is no basis to apply BS4 or assess the phenocopy and multiple-pathogenic-variant caveats.
Lack of segregation in affected members of a family.
The supplied case evidence does not provide a systematic gene-level comparison showing that IDH1 disease is caused primarily by truncating variants. Recurrent missense disease-associated variants are documented, but that alone does not establish the converse BP1 requirement or quantify the truncating-versus-missense disease mechanism.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The BP2 requirement cannot be assessed from the available evidence. No affected-proband or family observation documents NM_005896.4:c.395G>A in trans with a pathogenic variant in a fully penetrant dominant gene/disorder, and no observation documents it in cis with a pathogenic variant. No phase-testing result is available.
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.
The available records do not identify this variant in a specific patient with an alternate molecular basis for that patient's disease. Somatic cancer reports, disease labels, and functional studies do not establish the BP5 case-level finding.
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_005896.4:c.395G>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132His). 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 IDH1, 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
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_005896.4:c.395G>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132His). 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 IDH1, 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_005896.4:c.395G>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132His). 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 IDH1, 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_005896.4:c.395G>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132His). 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 IDH1, 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 IDH1, mapped onto the exon structure of NM_005896.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish1 / 29,606 | 3.4e-05 |
| European (Finnish)2 / 63,862 | 3.1e-05 |
| East Asian1 / 44,886 | 2.2e-05 |
| Admixed American1 / 59,976 | 1.7e-05 |
| South Asian1 / 91,068 | 1.1e-05 |
| European (non-Finnish)10 / 1,179,862 | 8.5e-06 |
This variant is present in gnomAD v4.1 (AF= 9.91615e-06; MAF= 0.00099%, 16/1613530 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Scope was settled first: NM_005896.4:c.395G>A is a missense variant producing NP_005887.2:p.(Arg132His), so the generic PP3/BP4 missense path uses REVEL only; SpliceAI and BayesDel are not used for this criterion. The REVEL score is 0.852, which meets the supplied generic PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932. Therefore PP3 is met at moderate strength. The calibrated threshold is from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
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)
Scope was settled first: NM_005896.4:c.395G>A is a missense variant producing NP_005887.2:p.(Arg132His), so the generic BP4 missense path uses REVEL only; the SpliceAI result cannot substitute for a gray-zone or non-supportive REVEL result. The REVEL score is 0.852, which does not meet any supplied generic BP4 threshold (supporting <= 0.29, moderate <= 0.183, or strong <= 0.016). Therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
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_005896.4:c.395G>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132His). 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 IDH1, 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 = 0.04). REVEL score = 0.852. BayesDel score = 0.187829.
7 paper records listed. 5 cited in the classification.
To determine whether the altered enzyme properties resulting from R132H mutation were shared by other R132 mutations found in human gliomas, recombinant R132C, R132L and R132S mutant IDH1 proteins were generated and the enzymatic properties assessed. Similar to R132H mutant protein, R132C, R132L, and R132S mutations all result in a gain-of-function for NADPH-dependent reduction of αKG.
Location Results, section describing enzymatic properties of R132 mutants
Context Stable expression and metabolite profiling in glioblastoma cell lines; purified recombinant IDH1 enzyme assays; LC-MS analysis of 2-hydroxyglutarate; crystallographic analysis of R132H IDH1; human glioma specimens.
IDH1R132H overexpression in established glioma cell lines in vitro resulted in a marked decrease in proliferation, decreased Akt phosphorylation, altered morphology, and a more contact-dependent cell migration.
Location Abstract; Results, Proliferation; Altered Enzymatic Activity of IDH1R132H-GFP Is Increased in the Presence of IDH1wt-GFP
Context Stable IDH1R132H-GFP overexpression in U87, U138, and HEK cell lines; proliferation, cell-cycle, migration, phospho-AKT, purified-enzyme, D-2-hydroxyglutarate, and intracranial SCID-mouse assays.
Expression of mutant but not wild-type IDH1 in human astrocytes resulted in the production of 2-HG
Location Results, paragraph describing Figure 1b; Figure 1 legend; Figure 2b; Figure 4
Context Isogenic immortalized human astrocytes expressing wild-type IDH1, mutant IDH1 R132H, or neither; methylation profiling, histone-mark, 5hmC/TET2, gene-expression, and neurosphere assays, with analysis of glioma tumors.
However, serum 2HG levels were elevated approximately tenfold in both young (7–16 weeks old) and older (47–56 weeks old) LysM-KI mice.
Location Results, paragraphs describing LysM-KI mice; Conclusions
Context Conditional Idh1R132H knock-in mice using LysMCre or VavCre, with metabolite measurements, flow cytometry, serial colony formation, DNA methylation sequencing, gene-expression profiling, and histone immunoblotting.
In multiple independent experiments, TF-1 cells expressing IDH1 R132H became cytokine-independent 12-16 days (4 passages) after infection.
Location Results, paragraph describing Figure 1C–1E; additional findings in Figure 1F and Figures 4D–4H
Context Stable lentiviral expression of HA-tagged wild-type IDH1, IDH1 R132H, or catalytically inactive IDH1 R132H/3DN in TF-1 and SCF ER-Hoxb8 murine progenitor cells; assays of 2-HG, cytokine independence, and differentiation.
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= 9.91615e-06; MAF= 0.00099%, 16/1613530 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37769e-05; MAF= 0.00338%, 1/29606 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251268 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16254 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 156444)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.852. BayesDel score = 0.187829.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61615239, n = 5513 times).
This variant lies in a statistically significant hotspot.