rs137852239

Positions:

• chrX-139551196-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000133.4(F9):​c.655C>T​(p.Gln219Ter) 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F9 NM_000133.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.208

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 11 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
• PP5: Variant X-139551196-C-T is Pathogenic according to our data. Variant chrX-139551196-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10589.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F9	NM_000133.4	c.655C>T	p.Gln219Ter	stop_gained	6/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.541C>T	p.Gln181Ter	stop_gained	5/7		NP_001300842.1
F9	XM_005262397.5	c.526C>T	p.Gln176Ter	stop_gained	5/7		XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.655C>T	p.Gln219Ter	stop_gained	6/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.541C>T	p.Gln181Ter	stop_gained	5/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1322C>T		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Benign	0.97
FATHMM_MKL	Benign	0.021	N
MutationTaster	Benign	1.0	A;A
Vest4		0.72
GERP RS		-1.9

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: rs137852239; hg19: chrX-138633355;