chrX-139561694-G-A

Position:

• chrX-139561694-G-A

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.1009G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 337 (p.Ala337Thr). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been reported in at least 8 unique probands with mild to severe hemophilia B (PMID:8091381; PMID:11013449; PMID:2726481), meeting phenotypic criteria for F9. The computational predictor REVEL gives a score of 0.783, 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_Very Strong + PM2_Supporting + PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA414445354/MONDO:0010604/080

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.54

Genes affected

F9 (HGNC:3551): (coagulation factor IX) This gene encodes vitamin K-dependent coagulation factor IX that circulates in the blood as an inactive zymogen. This factor is converted to an active form by factor XIa, which excises the activation peptide and thus generates a heavy chain and a light chain held together by one or more disulfide bonds. The role of this activated factor IX in the blood coagulation cascade is to activate factor X to its active form through interactions with Ca+2 ions, membrane phospholipids, and factor VIII. Alterations of this gene, including point mutations, insertions and deletions, cause factor IX deficiency, which is a recessive X-linked disorder, also called hemophilia B or Christmas disease. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.1009G>A	p.Ala337Thr	missense_variant	8/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.895G>A	p.Ala299Thr	missense_variant	7/7		NP_001300842.1
F9	XM_005262397.5	c.880G>A	p.Ala294Thr	missense_variant	7/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.1009G>A	p.Ala337Thr	missense_variant	8/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.895G>A	p.Ala299Thr	missense_variant	7/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1676G>A		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Apr 26, 2024

The c.1009G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 337 (p.Ala337Thr). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been reported in at least 8 unique probands with mild to severe hemophilia B (PMID: 8091381; PMID: 11013449; PMID: 2726481), meeting phenotypic criteria for F9. The computational predictor REVEL gives a score of 0.783, 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_Very Strong + PM2_Supporting + PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023). -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.074	T;T
Sift4G	Benign	0.081	T;T
Polyphen		0.98	D;.
Vest4		0.42
MutPred		0.94		Loss of stability (P = 0.0759);.;
MVP		0.98
MPC		1.6
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852253; hg19: chrX-138643853;