rs137852253

Variant names:

• chrX-139561694-G-A
• rs137852253
• NM_000133.4:c.1009G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-139561694-G-A
• chrX-139561694-G-C

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4 PP3 PM2_Supporting

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
• Publications: 2 publications found

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]

F9 Gene-Disease associations (from GenCC):

• hemophilia B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia B

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia B in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• thrombophilia, X-linked, due to factor 9 defect

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
F9	NM_000133.4	c.1009G>A	p.Ala337Thr	missense_variant	Exon 8 of 8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.895G>A	p.Ala299Thr	missense_variant	Exon 7 of 7		NP_001300842.1
F9	XM_005262397.5	c.880G>A	p.Ala294Thr	missense_variant	Exon 7 of 7		XP_005262454.1

Ensembl

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

Apr 26, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;.
PhyloP100		7.5
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
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852253; hg19: chrX-138643853;