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_000133.3(F9):c.1095A>G (p.Ser365=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10529870

368002 (ClinVar)

Gene: F9

Condition: hemophilia B

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 565fc8ba-d4a0-42b7-a317-4db5d2751962

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_000133.3:c.1095A>G

NM_000133.3(F9):c.1095A>G (p.Ser365=)

NC_000023.11:g.139561780A>G

CM000685.2:g.139561780A>G

NC_000023.10:g.138643939A>G

CM000685.1:g.138643939A>G

NC_000023.9:g.138471605A>G

NG_007994.1:g.36045A>G

ENST00000218099.7:c.1095A>G

ENST00000643157.1:n.1723+39A>G

ENST00000218099.6:c.1095A>G

ENST00000394090.2:c.981A>G

NM_001313913.1:c.981A>G

NM_000133.4:c.1095A>G

NM_001313913.2:c.981A>G

Benign

BA1 BP7 BP4

PS4 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 NM_000133.3:c.1095A>G variant predicts a synonymous change, Ser365=. It is reported at a high frequency of 0.03271 (622/19015 alleles with 172 hemizygotes) in the African subpopulation in gnomAD v2.1.1, meeting the BA1 cut-off of >=0.0000556. The variant is not predicted to impact splicing, and the nucleotide position at which this variant occurs is not highly conserved, meeting the BP4 and BP7 criteria. To the best of our knowledge, the variant has not been reported in male patients with Hemophilia B. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4, BP7.

BA1

The variant is reported at a frequency of 0.03271 (622/19015 alleles with 172 hemizygotes) in gnomAD v2.1.1 and at a frequency of 0.03197 (1000/31280 alleles with 269 hemizygotes) in gnomAD v3, in the African population. The reported MAFs are higher than the BA1 cut-off for F9 determined by the CFD VCEP: >=0.0000556

BP7

HSF and MES predict no impact on splicing. HSF predicts creation of cryptic splice sites, but there is no concordance with MES. The variant nucleotide is the reference in at least 3 mammals and the PhyloP score for this position is -1.77305 (from UCSC); therefore, the nucleotide is not conserved.

BP4

HSF and MES predict no impact on splicing.

PS4

PS4 not applied when variant meets BA1 or BS1. The variant is not reported in male patients with Hemophilia B in the literature, to the best of our knowledge. From internal laboratory data: the variant was identified in a male with moderate-severe Hemophilia B, with inhibitors. An alternate pathogenic variant in F9 was also identified in this patient.

PM1

The variant occurs in the peptidase S1 region, between aa position 227-459, which is determined to be a region critical to protein function by the CFD VCEP. However, PM1 has not been applied for this high-frequency variant.

Curation History

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