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_000133.4:c.1010C>T

CA414445371

Gene: F9 (HGNC:2158)

Condition: hemophilia B (MONDO:0010604)

Inheritance Mode: X-linked inheritance

UUID: aaacd397-4714-4f45-99e0-0ea67fd5c209

Approved on: 2024-04-26

Published on: 2024-07-11

HGVS expressions

NM_000133.4:c.1010C>T

NC_000023.11:g.139561695C>T

CM000685.2:g.139561695C>T

NC_000023.10:g.138643854C>T

CM000685.1:g.138643854C>T

NC_000023.9:g.138471520C>T

NG_007994.1:g.35960C>T

ENST00000218099.7:c.1010C>T

ENST00000643157.1:n.1677C>T

ENST00000218099.6:c.1010C>T

ENST00000394090.2:c.896C>T

NM_000133.3:c.1010C>T

NM_001313913.1:c.896C>T

NM_001313913.2:c.896C>T

Pathogenic

PS4 PM6 PM2_Supporting PP3 PP4_Moderate

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.1010C>T (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by valine at amino acid 337 (p.Ala337Val). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant is reported in at least 4 unique probands with mild hemophilia B (PMID: 33760382; PMID: 29296726; PMID: 9450791), meeting phenotypic criteria for F9, including at least one patient with with assumed de novo occurrence (PMID: 9450791). The computational predictor REVEL gives a score of 0.727, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (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: PS4 + PP4_Moderate + PM2_Supporting + PP3 + PM6. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023).

PS4

Refresh 4/1/24: This variant is reported in at least 5 unique probands with mild FIX deficiency (PMID: 33760382; PMID: 29296726; PMID: 9450791), meeting phenotypic criteria for F9 PS4 and PP4_Moderate. Count probands from MLOF (2 to bring to PS4_st). Potentially 4 patients with mild Hemophilia B from PMID: 29296726 may be added. But 1 patient from PMID: 9450791 meets F9 phenotype criteria, meeting PS4_Supporting at the time.

PM6

1 male patient from the US (9240) with mild Hemophilia B in PMID: 9450791. Authors report that family studies were performed, which revealed that the variant was de novo in the maternal grandfather of the patient. (APM reviewed paper and agree PM6_mod)

PM2_Supporting

The c.1010C>T (p.Ala337Val) variant is completely absent in gnomAD v2.1.1 & gnomAD v3.

PP3

The variant has a REVEL score of 0.727 (>0.6) and a CADD score of 25.8 (>21). SpliceAI predicts no splicing impact with scores <=0.2.

PP4_Moderate

MLOF patients reported to have FIX:C <50% at baseline. EAHAD database reports that the three patients had FIX:C levels of 6%, 7% and 7%. 2 probands counted towards PS4 and 1 proband counted for PP4.

PM1

Variant refresh 4/1/24: Variant no longer qualifies for PM1. The variant affects the Peptidase S1 domain (aa 227-459) in the F9 protein deemed critical for protein function by the CFD-VCEP.

Curation History

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