X-139548455-C-T

Position:

• chrX-139548455-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000133.4(F9):​c.484C>T​(p.Arg162Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.54

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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-139548455-C-T is Pathogenic according to our data. Variant chrX-139548455-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F9	NM_000133.4	c.484C>T	p.Arg162Ter	stop_gained	5/8	ENST00000218099.7
F9	NM_001313913.2	c.370C>T	p.Arg124Ter	stop_gained	4/7
F9	XM_005262397.5	c.392-2607C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F9	ENST00000218099.7	c.484C>T	p.Arg162Ter	stop_gained	5/8	1	NM_000133.4	P1
F9	ENST00000394090.2	c.370C>T	p.Arg124Ter	stop_gained	4/7	1
F9	ENST00000643157.1	n.1151C>T		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1990	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 11, 2018

The F9 c.484C>T; p.Arg162Ter variant (rs137852272), also known as Arg116Ter, has been described in multiple individuals affected with severe hemophilia B (see link to F9 database and references therein, Lin 2018). It contains and entry in ClinVar (Variation ID: 10640) and 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. Based on available information, this variant is considered pathogenic. REFERENCES Link to F9 database: http://www.factorix.org/ Lin X et al. Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population. Int J Lab Hematol. 2018 Apr;40(2):215-228. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2023

This sequence change creates a premature translational stop signal (p.Arg162*) in the F9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F9 are known to be pathogenic (PMID: 20301668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hemophilia B (PMID: 32875744). This variant is also known as 17,761C>T 116R>stop. ClinVar contains an entry for this variant (Variation ID: 10640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.58		Position offset: 36

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852272; hg19: chrX-138630614; COSMIC: COSV54379384; COSMIC: COSV54379384;