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.839T>G

CA414444922

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: aaebf2da-2342-4529-a13a-f304b530bb8a

Approved on: 2024-10-11

Published on: 2024-11-01

HGVS expressions

NM_001313913.2:c.839T>G

NC_000023.11:g.139561638T>G

CM000685.2:g.139561638T>G

NC_000023.10:g.138643797T>G

CM000685.1:g.138643797T>G

NC_000023.9:g.138471463T>G

NG_007994.1:g.35903T>G

ENST00000218099.7:c.953T>G

ENST00000643157.1:n.1620T>G

ENST00000218099.6:c.953T>G

ENST00000394090.2:c.839T>G

NM_000133.3:c.953T>G

NM_001313913.1:c.839T>G

NM_000133.4:c.953T>G

Likely Pathogenic

PM6 PM5 PS4_Moderate PP3 PP4_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 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.953T>G; p.Leu318Arg variant is completely absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). This missense variant has a REVEL score of 0.979 and meets PP3 criteria (PP3, threshold >0.6). At least 3 patients are reported in the literature with severe hemophilia B and this variant, meeting F9 phenotype criteria (PS4_Moderate, PP4_Moderate; PMID: 29296726, PMID: 1897528, PMID: 12588353). There is at least 1 proband with hemophilia B meeting phenotypic criteria for F9, with assumed de novo (maternity not confirmed in an affected male) occurrence (PM6, PMID: 30648777). Leu318Phe is another pathogenic variant at the same residue (PM5). In summary, this variant meets criteria to be classified as likely pathogenic. The ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel, for F9: PM5, PM6, PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting.

PM6

Variant reported de novo in a maternal grandfather in the family known as HB143 in PMID: 8434583. The same case was also reported in Bottema, at al 1991, which was used for evidence for PS4.

PM5

The F9 p.Leu318Phe variant meets the Coagulation Factor Deficiency VCEP classification for pathogenic.

PS4_Moderate

Variant identified in at least two probands with severe hemophilia B (PMID: 1897528, PMID: 12588353).

PP3

REVEL score is 0.979, which is above 0.6 cutoff.

PP4_Moderate

1 proband with severe hemophilia B from PMID: 29296726 meets F9 phenotype criteria

PM2_Supporting

Absent from gnomAD v2.1.1 and v3.1.

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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