Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: F8 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000132.4(F8):c.3169G>A (p.Glu1057Lys)

CA255144

10251 (ClinVar)

Gene: F8
Condition: hemophilia A
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: 58af8823-4b67-4d90-98e2-7e6cc5a759f0
Approved on: 2025-05-02
Published on: 2025-05-02

HGVS expressions

NM_000132.4:c.3169G>A
NM_000132.4(F8):c.3169G>A (p.Glu1057Lys)
NC_000023.11:g.154930621C>T
CM000685.2:g.154930621C>T
NC_000023.10:g.154158896C>T
CM000685.1:g.154158896C>T
NC_000023.9:g.153812090C>T
NG_011403.1:g.97103G>A
NG_011403.2:g.97103G>A
ENST00000360256.9:c.3169G>A
ENST00000647125.1:c.*2835G>A
ENST00000360256.8:c.3169G>A
NM_000132.3:c.3169G>A
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Benign

Met criteria codes 3
BA1 PP3 BS2
Not Met criteria codes 2
PS3 PS4

Evidence Links 1

Expert Panel

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 c.3169G>A variant in F8 is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 1057 (p.Glu1057Lys), affecting the B domain. The highest population minor allele frequency in gnomAD v2.1.1 is 0.006666 (99/14852 alleles) in the East Asian population with 28 hemizygotes, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1. The computational predictor REVEL gives a score of 0.651, which is above the CFD VCEP threshold of >=0.6, evidence that correlates with impact to F8 function (PP3). This variant was also identified in a proband with a diagnosis of hemophilia B and not hemophilia A, so the BS2 code was applied. In summary, this variant is classified as a benign for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel (version 1.0.0, released 10/5/2023): BA1, BS2, PP3.
Met criteria codes
BA1
The highest population minor allele frequency in gnomAD v2.1.1 is 0.006666 (99/14852 alleles) in the East Asian population with 28 hemizygotes and grpmax for exomes = 0.005941, 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 v4.1.1 is 0.01303 (440/33773 alleles) with 147 hemizygotes.
PP3
The computational predictor REVEL gives a score of 0.651, which is above the CFD VCEP threshold of >=0.6, evidence that correlates with impact to F8 function (PP3).
BS2
One MLOF patient with Hemophilia B was found to harbor this variant. Since this proband did not also carry a diagnosis of hemophilia A, we know that this proband had a normal factor VIII activity level.
Not Met criteria codes
PS3
1 stage clotting assay in HEK293T cells showed reduced FVIII:C levels of 42%, which is above our cutoff for use (PMID: 24108539).
This variant was transiently expressed in HEK293T cells and showed reduced FVIII:C 1 stage clotting assay of 42% and FVIII:Ag about 50%, corresponding to mild HA (Figure 2B) and reduced thermostability, below 6 min (WT=8.5 min). PubMed:24108539
PS4
This variant has been reported in 3 probands meeting phenotypic criteria for hemophilia A (PS4_moderate; PMID: 1924291, PMID: 19719548, PMID: 30913330). However, PS4 cannot be applied unless it meets very strong weight (8 cases) since over 3 males are found in gnomAD with this variant.
Curation History
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