The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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CA414447533

Gene: F9
Condition: hemophilia B
Inheritance Mode: X-linked inheritance
UUID: 63fb42c1-a20e-439a-a083-1172c25353eb
Approved on: 2024-04-26
Published on: 2024-07-11

HGVS expressions

NM_001313913.2:c.1245G>A
NC_000023.11:g.139562044G>A
CM000685.2:g.139562044G>A
NC_000023.10:g.138644203G>A
CM000685.1:g.138644203G>A
NC_000023.9:g.138471869G>A
NG_007994.1:g.36309G>A
ENST00000218099.7:c.1359G>A
ENST00000643157.1:n.1723+303G>A
ENST00000218099.6:c.1359G>A
ENST00000394090.2:c.1245G>A
NM_000133.3:c.1359G>A
NM_001313913.1:c.1245G>A
NM_000133.4:c.1359G>A
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Pathogenic

Met criteria codes 5
PM6 PM2_Supporting PVS1_Moderate PP4_Moderate PS4

Evidence Links 0

Expert Panel

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 variant c.1359G>A (p.Trp453Ter) introduces a premature stop codon in the last exon and is predicted to result in a truncated protein with more than 90% of the protein intact. This variant has been reported in at least 5 probands with severe hemophilia B, including as a de novo occurrence with assumed maternity and paternity, meeting phenotypic criteria for F9 (PMID: 36347023; PMID: 10698280; PMID: 8091381; PMID: 29296726). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria are applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1_moderate + PM2 supporting + PS4 + PP4_Moderate. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0, Released 10/5/2023).
Met criteria codes
PM6
1 Hemophilia B patient from PMID: 30648777 meets criteria for PM6
PM2_Supporting
The variant is absent from gnomAD v2.1.1 and v3 and meets criteria for PM2_Supporting
PVS1_Moderate
Refresh 4/2/24: Previously applied PVS1 strong (I think because peptidase domain met PM1), I downgraded to PVS1_mod because PM1 can no longer be applied to peptidase domain and this premature stop codon results in 2% truncation of protein (452/461). The nonsense variant occurs in the last exon and NMD is not predicted. The residue falls within amino acid positions 227-459 encoding the Peptidase S1 domain, which is recognized as a region critical to protein function by the CFD VCEP. Therefore, PVS1_Strong is applied.
PP4_Moderate
Patient from MLOF/Versiti cohort with severe FIX (MLOF does del dup and sequencing)
PS4
Refresh 4/2/24: This variant been reported in at least 5 probands (>4 probands & 0 gnomAD alleles) meeting phenotypic criteria for F9 (PMID: 36347023; PMID: 10698280; PMID: 8091381; PMID: 29296726) Probands counted: Wulff 2, MLOF 1, Saad 1, Liu 1 which is greater than 4, upgraded to PS4 Strong 3 Hemophilia B patients from PMIDs: 10698280 and 8091381 meet F9 phenotype criteria, meeting PS4_Moderate
Curation History
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