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.316G>A (p.Gly106Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA255329

10579 (ClinVar)

Gene: F9

Condition: hemophilia B

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 36950276-dd4c-48f7-ba60-d0c1aa45b4d6

Approved on: 2024-02-09

Published on: 2024-07-11

HGVS expressions

NM_000133.3:c.316G>A

NM_000133.3(F9):c.316G>A (p.Gly106Ser)

NC_000023.11:g.139541114G>A

CM000685.2:g.139541114G>A

NC_000023.10:g.138623273G>A

CM000685.1:g.138623273G>A

NC_000023.9:g.138450939G>A

NG_007994.1:g.15379G>A

ENST00000218099.7:c.316G>A

ENST00000218099.6:c.316G>A

ENST00000394090.2:c.277+3728G>A

ENST00000479617.2:n.269G>A

NM_001313913.1:c.277+3728G>A

NM_000133.4:c.316G>A

NM_001313913.2:c.277+3728G>A

Pathogenic

PP1 PP3 PM1 PP4_Moderate PS4

PM2 PM5 BS1

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.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein, meeting the PM1 criteria. This missense variant has a REVEL score of 0.905(>0.6), meeting the PP3 criteria. It is reported at an MAF of 0.00002441 (5/204867 alleles) in the overall population in gnomAD v2.1.1, with 3 hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met. Over 60 patients with mild and moderate hemophilia B are reported in the literature meeting PS4_Very strong and PP4_Moderate criteria (PMID: 22103590, 29296726). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very strong, PM1, PP4_Moderate, PP3.

PP1

Two brothers are reported with the Gly106Ser variant and mild hemophilia B. They have a positive family history, with an affected maternal uncle who was not genotyped.

PP3

The c.316G>A (p.Gly106Ser) missense variant has a REVEL score of 0.905(>0.6)

PM1

The c.316G>A (p.Gly106Ser) variant affects one of the functional domains (aa 93-129; EGF-like 1 domain) in the F9 protein and meets criteria for PM1.

PP4_Moderate

Male with mild hemophilia B with 16% factor IX activity level who had F8 and F9 full gene sequencing with deletion/duplication analysis.

PS4

21 patients with mild and moderate hemophilia B reported in PMID: 22103590 meet F9 phenotype criteria and are counted towards PS4_Very Strong. Several additional probands are reported in the literature and EAHAD notes 150 patients, but the maximum threshold for PS4_Very Strong has been reached. A founder effect is suggested for this variant as several patients of European descent analyzed in the US share 3 common haplotypes (PMID: 1916816). 3 males are reported in gnomAD, so this variant current meets the criteria for application of PS4.

PM2

The variant is reported in gnomAD v2.1.1. is 3 hemizygotes and does not meet criteria for PM2_Supporting.

PM5

Gly106Arg, Gly106Cys, Gly106Asp are variants at the same residue. These are not evaluated by the CFD-VCEP yet.

BS1

The c.316G>A (p.Gly106Ser) variant is reported at an MAF of 0.00002441(5/204867 alleles) in the overall population ingnomAD v2.1.1, with 3hemizygotes; however BS1 criteria of MAF >=0.0000278 is not met.

Curation History

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