X-139561694-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1009G>C (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by proline at amino acid 337 (p.Ala337Pro). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been previously reported in at least one patient with mild hemophilia B (PMID:1998585), meeting phenotypic criteria for F9. An additional proband with severe hemophilia B has been reported in the EAHAD Factor IX (F9) variant database. The computational predictor REVEL gives a score of 0.617, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). Different missense variants causing a change at the same residue (p.Ala337Thr and p.Ala337Val) have been established as pathogenic for F9 and SpliceAI predicts no impact on splicing meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Moderate + PM2_Supporting + PP3 + PM5. (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/CA255378/MONDO:0010604/080

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• 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: Likely_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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000133.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	NM_000133.4	MANE Select	c.1009G>C	p.Ala337Pro	missense	Exon 8 of 8	NP_000124.1
	F9	NM_001313913.2		c.895G>C	p.Ala299Pro	missense	Exon 7 of 7	NP_001300842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F9	ENST00000218099.7	TSL:1 MANE Select	c.1009G>C	p.Ala337Pro	missense	Exon 8 of 8	ENSP00000218099.2
	F9	ENST00000394090.2	TSL:1	c.895G>C	p.Ala299Pro	missense	Exon 7 of 7	ENSP00000377650.2
	F9	ENST00000643157.1		n.1676G>C		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary factor IX deficiency disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	-1.7	N
PhyloP100		7.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.4	N
REVEL	Uncertain	0.62
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.014	B
Vest4		0.58
MutPred		0.90		Gain of methylation at K339 (P = 0.0595)
MVP		0.99
MPC		1.9
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.99
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;