Variant: NM_000132.4(F8):c.2840C>G (p.Pro947Arg)

CA10568278

1685797 (ClinVar)

Gene: F8

Condition: hemophilia A

Inheritance Mode: X-linked inheritance

UUID: 0fc2bdbc-0a64-452e-a356-311717e7520c

Approved on: 2025-05-02

Published on: 2025-05-02

HGVS expressions

NM_000132.4:c.2840C>G
NM_000132.4(F8):c.2840C>G (p.Pro947Arg)
NC_000023.11:g.154930950G>C
CM000685.2:g.154930950G>C
NC_000023.10:g.154159225G>C
CM000685.1:g.154159225G>C
NC_000023.9:g.153812419G>C
NG_011403.1:g.96774C>G
NG_011403.2:g.96774C>G
ENST00000360256.9:c.2840C>G
ENST00000647125.1:c.*2506C>G
ENST00000360256.8:c.2840C>G
NM_000132.3:c.2840C>G

Likely Benign

• Met criteria codes: PS3 BA1

• Not Met criteria codes: BP4 PP3

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

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.2840C>G variant in F8 is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 947 (p.Pro947Arg). In gnomAD v2.1.1, the Grpmax total for exomes is 0.0003539 and for genomes is 0.0003564, which are both higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>0.000333) for BA1. In gnomAD v3.1.2, the Grpmax total for genomes is 0.0007292, which is also above the cut off to apply BA1. An one stage clotting assay in HEK293T cells showed reduced FVIII:C of about 30% indicating that this variant impacts protein function (PMID: 24108539)(PS3). The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging (>=0.6) or benign impact (<=0.3) on F8 function. this variant is classified as a likely benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1, PS3.

Met criteria codes

• PS3: 1 stage clotting assay in HEK293T cells showed reduced FVIII:C of about 30% (cutoff <40%) indicating that this variant impacts protein function (PMID: 24108539)(PS3).
• BA1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007724 (11/14242 alleles) in the East Asian population with grpmax for genomes = 0.0003539 and grpmax for exomes = 0.0003564, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>0.000333) for BA1, and therefore meets this criterion (BA1). The highest MAF in gnomAD v4.1.0 is 0.0004754 (16/33657 alleles) in the East Asian population.

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging (>=0.6) or benign impact (<=0.3) on F8 function.
• PP3: The computational predictor REVEL gives a score of 0.578, which is neither above nor below the thresholds predicting a damaging (>=0.6) or benign impact (<=0.3) on F8 function.