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_001313913.2:c.689G>A

CA414443541

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: 6e32ad07-8030-4bf1-a955-0c857e980a91

Approved on: 2025-10-03

Published on: 2025-10-07

HGVS expressions

NM_001313913.2:c.689G>A

NC_000023.11:g.139560820G>A

CM000685.2:g.139560820G>A

NC_000023.10:g.138642979G>A

CM000685.1:g.138642979G>A

NC_000023.9:g.138470645G>A

NG_007994.1:g.35085G>A

ENST00000218099.7:c.803G>A

ENST00000643157.1:n.1470G>A

ENST00000218099.6:c.803G>A

ENST00000394090.2:c.689G>A

NM_000133.3:c.803G>A

NM_001313913.1:c.689G>A

NM_000133.4:c.803G>A

Pathogenic

PS2_Very Strong PS4 PP3 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 F9 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Coagulation Factor Deficiency VCEP

The c.803G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 268 (p.Cys268Tyr). This variant has been previously reported in 4 patients with severe FIX deficiency, including at least 2 probands with de novo occurrence (maternity and paternity confirmed in a carrier female/maternity confirmed in an affected male) (PMID: 30648777; PMID: 30210749; PMID: 34590426), meeting PS4 and PS2_Very strong. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3.1/ gnomAD v4.1.0), meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.989, which is above the threshold of 0.6, evidence that correlates with impact to F9 function, meeting PP3. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS2_Very Strong, PS4, PM2_Supporting, PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023)

PS2_Very Strong

There are 2 probands with isolated reduction in FIX activity levels meeting phenotypic criteria for F9, with confirmed de novo (maternity and paternity confirmed in a carrier female/maternity confirmed in an affected male) occurrence. Using the SVI point system, each proband in Lu et al counts for 2 pts (4 pts total), meeting PS2_VS.

PS4

This variant has been reported in 4 probands (4-7 probands & 0 gnomAD alleles) meeting phenotypic criteria for F9.

PP3

The computational predictor REVEL gives a score of 0.989, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). This variant is predicted to have no impact on splicing based on SpliceAI in silico prediction scores (delta 0, 0, 0, 0).

PM2_Supporting

This variant is absent from males in population databases (gnomad v2.1.1, v3.1, and v4.1.0).

PM1

Variant is not within exons 3, 4 or 5.

Curation History

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