The TTR NM_000371.4:c.424G>A (NP_000362.1:p.(Val142Ile)) missense variant has previously been reported in somatic cancers (COSMIC; COSV99030963, n = 4 times). Experimental evidence: Two independent assays showed impaired TTR stability and aggregation, including threefold faster tetramer dissociation and turbidity 0.241 versus 0.046 AU (p<0.0001). 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.TTR encodes transthyretin, a protein that transports thyroid hormones in the blood and cerebrospinal fluid and helps carry vitamin A. Abnormal transthyretin can form amyloid deposits, causing inherited conditions that may affect the peripheral nerves, heart, eyes, brain coverings, or other tissues. TTR is not known to have a direct cancer association.
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, strong: two independent assays showed impaired TTR stability and aggregation, including threefold faster tetramer dissociation and turbidity 0.241 versus 0.046 AU (p<0.0001).
Met: affected/control counts yielded OR 9.08 (95% CI 2.35-35.03), satisfying the PS4 requirement of OR >5.0 with a confidence interval excluding 1.0.
Met at moderate strength: ClinVar documents pathogenic p.Val142Ala and likely pathogenic p.Val142Leu at the same residue.
Met at supporting: missense REVEL 0.645 meets the supplied PP3 supporting threshold of >=0.644.
Met: four patients with AL amyloidosis, an alternate molecular basis, also carried the TTR V122I allele.
Pathogenic: PS3 and PS4 strong plus PM5 moderate and PP3 supporting satisfy the generic ACMG/AMP 2015 rule requiring two strong criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1,433 / 1,614,082 alleles. Recorded AF 0.000887811. Recorded homozygote count 8.
This variant is present in gnomAD v2.1 (AF= 0.00153823; MAF= 0.15382%, 435/282792 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0162208; MAF= 1.62208%, 405/24968 alleles, homozygotes = 3); grpmax FAF= 0.0149723.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0013575152041702867, 25/18416 alleles, homozygotes = 0).
Recorded REVEL score: 0.645. Refer to the recorded PP3/BP4 rationale for interpretation.
42 Pathogenic · 3 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 previously been reported in somatic cancers (COSMIC; COSV99030963, n = 4 times).
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: 5 met · 8 not met · 10 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 is met from PMID:9017939: OR 9.075, approximate 95% CI 2.35-35.03, and 9.075 > 5.0? yes.
PP4 is not assessed because patient-specific phenotype and family history are missing.
PP5 and BP6 are not met because exact-variant ClinVar has zero expert-panel submissions.
BP5 is met from four AL amyloidosis cases also carrying TTR V122I, with human review requested.
This group evaluated only PP3 and BP4. The missense consequence selects the REVEL-only path; SpliceAI and BayesDel do not provide additional evidence for these criteria.
PP3 is met at supporting strength because REVEL 0.645 is at least 0.644; BP4 is not met because the same REVEL score is above 0.29.
No criteria match.
PS3 is met at strong strength. The variant is TTR p.Val142Ile, historically designated V122I in the mature-protein numbering used by Jiang et al. (PMID:11752443). In recombinant TTR experiments with wild-type comparators, V122I increased the tetramer dissociation rate approximately threefold and amyloid fibril formation approximately twofold, while selectively lowering tetramer stability. An independent study directly testing TTR-Val142Ile (PMID:35903975) in HEK293-EBNA-expressed and purified protein found substantially greater aggregation than wild type by turbidity (0.241 AU, SD 0.008 versus 0.046 AU, SD 0.002; p<0.0001) and greater Thioflavin T fluorescence (79.83 AU, SD 12.3 versus 17.63 AU, SD 3.59; p<0.0001). These concordant, biologically relevant, orthogonal functional readouts with wild-type controls demonstrate a damaging effect on TTR tetramer stability and amyloidogenicity. The evidence supports strong rather than very strong functional strength because the available studies are research assays rather than validated and reproducible clinical diagnostic laboratory assays.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met. PMID:9017939 reports the exact mature-protein V122I/Ile122 allele in 6/26 analyzable affected Black patients and 4/125 age-matched Black autopsy controls without amyloidosis. I computed the case-control OR as (6/20)/(4/121)=9.075 and the approximate Wald 95% CI as 2.35-35.03; the CI excludes 1.0. The governing operator is >5.0: 9.075 > 5.0? yes. PMID:19781421 independently reports 36/156 affected African American patients versus a reported population prevalence of 3-3.9%; using the midpoint 3.5% gives approximate OR 8.27, but no control count or CI is available, so it is supportive only.
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.
PM5 applies because the observed missense variant is p.Val142Ile and ClinVar's cited pathogenicity evidence documents different missense changes at the same codon, p.Val142Ala and p.Val142Leu, as pathogenic or likely pathogenic with strong evidence. The pathogenic p.Val142Ala comparator is sufficient for the same-residue criterion.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The variant is a missense SNV, NM_000371.4:c.424G>A (p.Val142Ile), so the generic rule requires the missense path and REVEL only. REVEL is 0.645, which meets the supplied ClinGen SVI supporting threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for PP3 in this missense situation, and BayesDel is not usable because no generic ACMG-strength calibration is established. The ACMG/AMP computational definition is therefore met at supporting strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP5 is met. The PMID:19781421 abstract reports that four patients with AL amyloidosis also carried the TTR V122I allele. AL amyloidosis is an alternate molecular basis for amyloid disease relative to TTR-mediated hereditary amyloidosis, and the exact V122I allele was present in those cases. Human review is requested because only the abstract was available.
Variant found in a case with an alternate molecular basis for disease.
PS1 requires the same amino acid change to have been established as pathogenic regardless of nucleotide change. The case documents NM_000371.4:c.424G>A / p.Val142Ile itself as pathogenic, but the ClinVar submission states that the same nucleotide change was previously reported; it does not establish an alternate nucleotide change producing p.Val142Ile. Therefore, the required different-nucleotide same-amino-acid evidence is not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM2 is not met under the generic rule. The default all-comers population source applies because no VCEP governs TTR in this case. gnomAD v4.1 reports an overall AF of 0.000887811 (1,433/1,614,082 alleles; 8 homozygotes), which exceeds the supplied generic PM2 supporting threshold of <=0.0001. The older non-cancer exome subset also contains the variant at AF 0.00112296 (266/236,874 alleles; 1 homozygote), and gnomAD v2.1 overall AF is 0.00153823; none supports PM2.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PP5 is not met under the required exact-variant ClinVar expert-panel restriction. The ClinVar audit reports 54 submissions and expert_panel_submissions=0; ordinary laboratory submissions and aggregate Pathogenic/Likely pathogenic labels cannot trigger PP5. PMID:22877808 is a literature report, not an exact-variant ClinVar expert-panel classification.
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 highest applicable all-comers population frequency is gnomAD v4.1 overall AF 0.000887811 (1,433/1,614,082 alleles; 8 homozygotes), well below the generic stand-alone threshold of 0.05. The gnomAD v2.1 overall AF is also only 0.00153823 (435/282,792 alleles). Although the African/African American frequency is elevated at 0.0169693 in gnomAD v4.1, it remains below 5% and therefore does not meet BA1.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS3 is not met. The available variant-specific functional studies do not show no damaging effect; instead, they show reduced TTR tetramer stability, faster dissociation, increased amyloid fibril formation, and increased aggregation relative to wild-type controls. No well-established benign functional or splicing result for TTR p.Val142Ile was identified in the reviewed evidence.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 is a missense-variant criterion for genes in which disease is primarily caused by truncating variants. The reviewed TTR evidence instead centers on amyloidogenic missense disease, including the Val142Ile variant and its destabilizing functional effect, so the gene-level premise for BP1 is not met.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense SNV, so BP4 must be judged using REVEL only; SpliceAI cannot substitute for the missense protein-impact path. REVEL is 0.645, above the supplied BP4 supporting threshold of <= 0.29 and within the stated gray zone for benign interpretation, so BP4 is not met. BayesDel is not usable 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)
BP6 is not met under the required exact-variant ClinVar expert-panel restriction. The ClinVar audit reports expert_panel_submissions=0 and no benign or likely-benign expert-panel classification. Ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No auditable case-level evidence establishes that NM_000371.4:c.424G>A arose de novo with both maternity and paternity confirmed. The available ClinVar record includes a submission annotated with origin "paternal", but it does not provide tested parental genotypes, maternity confirmation, paternity confirmation, family history, or a documented proband phenotype sufficient to apply PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM1 requires a mutational hotspot or critical and well-established functional domain without benign variation. The hotspot query reports no statistically significant hotspot. vcep_materials.json has no TTR domain_tables entry, and the reviewed evidence does not independently establish that residue 142 lies in a qualifying critical domain together with absence of benign variation. The criterion is therefore not assessed rather than treated as absent.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
No auditable case-level evidence establishes an assumed de novo occurrence of NM_000371.4:c.424G>A. The available record does not document a proband with a disease-consistent phenotype and the variant absent from the tested parents without confirmation of both maternity and paternity.
Assumed de novo, but without confirmation of paternity and maternity.
The available evidence does not provide an auditable pedigree with multiple affected family members, their phenotypes, their genotypes, and the number of informative meioses for NM_000371.4:c.424G>A. A literature summary describes autosomal-dominant transmission of a TTR-associated hyperthyroxinemia phenotype in eight individuals across three generations, but the underlying paper is not represented by an exact source_registry key or an available paper extraction, so it cannot be used as a citable segregation result here.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
PP2 requires both a low rate of benign missense variation and missense variants as a common disease mechanism. The evidence supports that TTR disease includes amyloidogenic missense variants, but it does not provide a gene-level benign-missense rate or an applicable threshold establishing the first component. The criterion is not assessed.
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 PP4 rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No patient-specific phenotype or family history sufficient to assess this requirement is available.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 is not assessed from the generic 1% default alone. The African/African American frequency is 0.0169693 in gnomAD v4.1 (1,273/75,018 alleles; 8 homozygotes), and the gnomAD v2.1 value is 0.0162208 (405/24,968 alleles; 3 homozygotes). This elevation is ancestry-concentrated and is consistent with the known TTR Val142Ile founder allele context. TTR Val142Ile-related amyloidosis is late-onset, so disease prevalence, penetrance, and allelic heterogeneity must be incorporated into a maximum-credible-frequency calculation before applying BS1. The case provides no validated prevalence, penetrance, or disease-model inputs sufficient to perform that calculation; therefore BS1 is not assessed rather than applied.
BS2 is not assessed. gnomAD v4.1 reports 8 homozygotes and gnomAD v2.1 reports 3 homozygotes, but the population records do not establish that these individuals were healthy adults, unaffected for the relevant late-onset TTR phenotype, or observed at an age sufficient to satisfy the full-penetrance early-age requirement. Because TTR Val142Ile-associated amyloidosis is late-onset, homozygote counts alone cannot satisfy 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.
No auditable family study identifies affected relatives who lack NM_000371.4:c.424G>A. The available evidence does not establish which relatives were affected, whether they were phenocopies, whether another pathogenic variant contributed to the phenotype, or how many informative non-segregating observations exist.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, fu
BP2 is applicable to a fully penetrant dominant gene/disorder when the evaluated variant is observed in trans with a pathogenic variant, or to any inheritance pattern when it is observed in cis with a pathogenic variant. The available evidence does not identify an affected proband carrying a second pathogenic variant at the relevant locus and provides no parental, offspring, molecular-phasing, or cis/trans observation. Consequently, the allelic observation required to assess BP2 is missing.
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.
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_000371.4:c.424G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val142Ile). 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 TTR, 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 evaluated variant to be detected in trans with a pathogenic variant, with phase established through parental or offspring testing. The available TTR V122I disease evidence describes affected individuals as heterozygous and does not establish a recessive TTR disorder or a required pathogenic allele in trans; therefore PM3 is not applicable. This conclusion does not use the presence of the variant in gnomAD homozygotes as phase or affected-proband evidence.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
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_000371.4:c.424G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val142Ile). 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 TTR, 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_000371.4:c.424G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val142Ile). 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 TTR, 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_000371.4:c.424G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val142Ile). 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 TTR, 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 TTR, mapped onto the exon structure of NM_000371.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American1273 / 75,018 | 0.0178 hom |
| Admixed American55 / 60,022 | 0.00092 |
| Remaining individuals57 / 62,508 | 0.00091 |
| Middle Eastern4 / 6,062 | 0.00066 |
| South Asian13 / 91,078 | 0.00014 |
| European (non-Finnish)30 / 1,180,020 | 2.5e-05 |
| East Asian1 / 44,868 | 2.2e-05 |
| African/African American405 / 24,968 | 0.0163 hom |
| Admixed American21 / 35,440 | 0.00059 |
| Remaining individuals3 / 7,228 | 0.00042 |
| South Asian2 / 30,616 | 6.5e-05 |
| European (non-Finnish)4 / 129,136 | 3.1e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000887811; MAF= 0.08878%, 1433/1614082 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0169693; MAF= 1.69693%, 1273/75018 alleles, homozygotes = 8); grpmax FAF= 0.0161943.
This variant is present in gnomAD v2.1 (AF= 0.00153823; MAF= 0.15382%, 435/282792 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0162208; MAF= 1.62208%, 405/24968 alleles, homozygotes = 3); grpmax FAF= 0.0149723.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0013575152041702867, 25/18416 alleles, homozygotes = 0).
The variant is a missense SNV, NM_000371.4:c.424G>A (p.Val142Ile), so the generic rule requires the missense path and REVEL only. REVEL is 0.645, which meets the supplied ClinGen SVI supporting threshold of >= 0.644 (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for PP3 in this missense situation, and BayesDel is not usable because no generic ACMG-strength calibration is established. The ACMG/AMP computational definition is therefore met at supporting strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense SNV, so BP4 must be judged using REVEL only; SpliceAI cannot substitute for the missense protein-impact path. REVEL is 0.645, above the supplied BP4 supporting threshold of <= 0.29 and within the stated gray zone for benign interpretation, so BP4 is not met. BayesDel is not usable 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)
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_000371.4:c.424G>A in TTR is a missense substitution predicted to produce NP_000362.1:p.(Val142Ile). 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 TTR, 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 = 0.645. BayesDel score = 0.0229274.
9 paper records listed. 4 cited in the classification.
The V122I mutation selectively acts by lowering the stability of the tetramer (Fig. 3) and consequently lowering the kinetic barrier for tetramer dissociation compared with WT TTR (Figs. 1C and 2B).
Location Results, paragraphs titled "The V122I Homotetramer Dissociates to Folded Monomers 3-Fold Faster than WT Homotetramers" and "The V122I Tetramer Is Destabilized Relative to WT"; Discussion
Context Recombinant wild-type and V122I TTR homotetramers and engineered monomeric TTR variants were evaluated using urea denaturation, pH-induced tetramer dissociation, turbidity, thioflavin-T fibril-formation, and structural stability assays.
All patients underwent full DNA sequencing to confirm the presence of V122I heterozygosity or wild-type TTR before inclusion in the study.
Location Appendix, Methods, Study patients; Results, Survival and cardiovascular hospitalization; Table I; Table III
Context Prospective observational TRACS cohort: 29 patients with biopsy-confirmed TTR cardiac amyloidosis, including 11 V122I ATTRm and 18 wild-type TTR, followed at six-month intervals for up to two years.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Location Introduction/Methods; Proposed Criteria for Interpretation of Sequence Variants
Context ACMG/AMP/CAP workgroup consensus process involving laboratory surveys, literature review, workshop input, and testing of the proposed classification scheme on previously classified variants.
TTR-Ala65Val (0.245, SD 0.006) as well as known pathogenic variants -V142I (0.241 AU, SD 0.008), -Val50Met (0.151 AU, SD 0.005) and -Phe53Leu (0.165 AU, SD 0.005) did show a significantly higher turbidity than wt-TTR (0.046 AU, SD 0.002) (p < 0.0001) (Fig. 2).
Location Table 1; Results, "Turbidity measurement and time course of wt-TTR, pathogenic variants and TTR-Ala65Val"; Results, "Thioflavin T staining"
Context In vitro testing of mammalian HEK293-EBNA cell-expressed and purified wild-type TTR and 12 TTR variants using turbidity and Thioflavin T fluorescence assays under defined buffer and temperature conditions.
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= 0.000887811; MAF= 0.08878%, 1433/1614082 alleles, homozygotes = 8) and has highest observed frequency in the African/African American population (AF= 0.0169693; MAF= 1.69693%, 1273/75018 alleles, homozygotes = 8); grpmax FAF= 0.0161943.
This variant is present in gnomAD v2.1 (AF= 0.00153823; MAF= 0.15382%, 435/282792 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0162208; MAF= 1.62208%, 405/24968 alleles, homozygotes = 3); grpmax FAF= 0.0149723.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0013575152041702867, 25/18416 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (42 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 13426)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.645. BayesDel score = 0.0229274.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99030963, n = 4 times).
This variant does not lie in a statistically significant hotspot.