Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000132.4:c.1420G>A

CA414914390

Gene: F8 (HGNC:2157)

Condition: hemophilia A (MONDO:0010602)

Inheritance Mode: X-linked inheritance

UUID: 3beb4702-1e52-4da0-bd95-488b63916bbc

Approved on: 2024-09-30

Published on: 2024-10-01

HGVS expressions

NM_000132.4:c.1420G>A

NC_000023.11:g.154965993C>T

CM000685.2:g.154965993C>T

NC_000023.10:g.154194268C>T

CM000685.1:g.154194268C>T

NC_000023.9:g.153847462C>T

NG_011403.1:g.61731G>A

NG_011403.2:g.61731G>A

ENST00000360256.9:c.1420G>A

ENST00000647125.1:c.*1296G>A

ENST00000360256.8:c.1420G>A

ENST00000483822.2:n.240G>A

NM_000132.3:c.1420G>A

Likely Pathogenic

PP4_Moderate PS1_Moderate PP3 PM5 PS4_Moderate PM2_Supporting

PM1

Evidence Links 0

Expert Panel

Coagulation Factor Deficiency VCEP

Criteria Specification Information

Criteria Specification: ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The variant, NM_000132.3(F8):c.1420G>A, predicts a missense change, Gly474Arg, which is not reported in gnomAD v2.1.1 or v3. This variant has been reported in at least three patients with severe or mild-moderate Hemophilia A in the literature (PMID: 9603440, 16972227, 29296726) meeting PS4_Moderate and PP4_Moderate criteria. The variant has a REVEL score of 0.972 (threshold >0.6) meeting criteria for PP3. Another nucleotide change at the same codon, c.1421G>A (p.Gly474Glu) is classified as pathogenic by CFD-VCEP meeting criteria for PM5. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PM5, PP4_Moderate, PP3, PM2_Supporting.

PP4_Moderate

1 patient with the c.1420G>A variant and severe hemophilia A (FVIII:C <1%) is reported in the MLOF study, wherein full gene sequencing of F8 and F9 and deletion/duplication analysis of F8 were performed.

PS1_Moderate

Another nucleotide change at the same position, c.1420G>T (p.Gly474Trp), is also reported. PS1_Moderate is applied as c.1420G>T is evaluated by the CFD-VCEP as a likely pathogenic.

PP3

REVEL score of 0.972 (threshold: >0.6) and CADD score of 27.5 (threshold: >21) meet criteria for PP3

PM5

Another nucleotide change at the same codon, c.1421G>A (p.Gly474Glu) is classified as pathogenic by CFD-VCEP, and it does not appear to causing a splicing defect (SpliceAI = Acceptor Gain 0.02).

PS4_Moderate

Two patients with severe and mild-moderate hemophilia A reported in PMID: 9603440 and PMID: 16972227, respectively, meeting F8 phenotype criteria.

PM2_Supporting

Gly474Arg (c.1420G>A) is absent from gnomAD v2.1.1 and v3.

PM1

Gly474Arg occurs in the A2 domain. PM1 is not applied at this time.

Curation History

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