rs137852250

Positions:

• chrX-139561577-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000218099.7(F9):​c.892C>T​(p.Arg298Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R298R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 ENST00000218099.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.47

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 140 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-139561577-C-T is Pathogenic according to our data. Variant chrX-139561577-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.892C>T	p.Arg298Ter	stop_gained	8/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.778C>T	p.Arg260Ter	stop_gained	7/7		NP_001300842.1
F9	XM_005262397.5	c.763C>T	p.Arg255Ter	stop_gained	7/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.892C>T	p.Arg298Ter	stop_gained	8/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.778C>T	p.Arg260Ter	stop_gained	7/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1559C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 19, 2019

The F9 c.892C>T; p.Arg298Ter variant (rs137852250), also known as Arg252Ter in the mature protein, is published in the medical literature in individuals with severe hemophilia B (Belvini 2005, Chen 1989, Jayandharan 2009). The variant is reported in the ClinVar database (Variation ID: 10603) but is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Belvini D et al. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica. 2005 May;90(5):635-42. Chen SH et al. Factor IXPortland: a nonsense mutation (CGA to TGA) resulting in hemophilia B. Am J Hum Genet. 1989 Apr;44(4):567-9. Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. -

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2023

This sequence change creates a premature translational stop signal (p.Arg298*) in the F9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acid(s) of the F9 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of F9-related conditions (PMID: 2929599, 22544209, 32155688, 32875744). This variant is also known as c.30875 (p.Arg252Ter). ClinVar contains an entry for this variant (Variation ID: 10603). For these reasons, this variant has been classified as Pathogenic. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.51	D
MutationTaster	Benign	1.0	A;A
Vest4		0.76
GERP RS		5.4

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: rs137852250; hg19: chrX-138643736; COSMIC: COSV54379173;