The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000133.4(F9):c.407T>C (p.Ile136Thr)

CA414438824

627177 (ClinVar)

Gene: F9
Condition: hemophilia B
Inheritance Mode: X-linked inheritance
UUID: 42c02c48-c3ed-4e7a-a05d-7d209d9c2d6c
Approved on: 2024-11-01
Published on: 2024-11-01

HGVS expressions

NM_000133.4:c.407T>C
NM_000133.4(F9):c.407T>C (p.Ile136Thr)
NC_000023.11:g.139548378T>C
CM000685.2:g.139548378T>C
NC_000023.10:g.138630537T>C
CM000685.1:g.138630537T>C
NC_000023.9:g.138458203T>C
NG_007994.1:g.22643T>C
ENST00000218099.7:c.407T>C
ENST00000643157.1:n.1074T>C
ENST00000218099.6:c.407T>C
ENST00000394090.2:c.293T>C
ENST00000479617.2:n.360T>C
NM_000133.3:c.407T>C
NM_001313913.1:c.293T>C
NM_001313913.2:c.293T>C
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Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS4 PP3 PM1

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
NM_000133.4(F9):c.407T>C (p.Ile136Thr) missense variant has a REVEL score of 0.634, which meets criteria for PP3. This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant occurs within exon 5, a region deemed critical for the encoded FIX protein by the CFD-VCEP, and meets criteria for PM1. The c.407T>C (p.Ile136Thr) variant is reported in at least two individuals with mild hemophilia B and two individuals with hemophilia B of unspecified severity (PMID: 8680410, 8091381, 31064749), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PS4, PM1, PP3, PM2_Supporting.
Met criteria codes
PM2_Supporting
The Ile136Thr missense variant is completely absent from gnomAD v2.1.1 and v3.1.2
PS4
The c.407T>C (p.Ile136Thr) variant is reported in at least two individuals with mild hemophilia B and two individuals with hemophilia B of unspecified severity (PMID: 8680410, 8091381, 31064749), meeting criteria for PS4.
PP3
This missense variant has a REVEL score of 0.634, meeting criteria for PP3 (threshold >0.6). SpliceAI predicts an acceptor gain at -15bp with a delta score of 0.02. PP3 threshold (>0.5) for splicing not met.
PM1
The variant, c.407T>C occurs within exon 5, a region deemed critical for the encoded FIX protein by the CFD-VCEP, and meets criteria for PM1.
Curation History
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