rs1556006174

Positions:

• chrX-139548489-C-CA

Variant summary

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

The NM_000133.4(F9):​c.519dup​(p.Val174SerfsTer15) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F9 NM_000133.4 frameshift, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.54

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 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-139548489-C-CA is Pathogenic according to our data. Variant chrX-139548489-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375452.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.519dup	p.Val174SerfsTer15	frameshift_variant, splice_region_variant	5/8	ENST00000218099.7	NP_000124.1
F9	NM_001313913.2	c.405dup	p.Val136SerfsTer15	frameshift_variant, splice_region_variant	4/7		NP_001300842.1
F9	XM_005262397.5	c.392-2572dup		intron_variant			XP_005262454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F9	ENST00000218099.7	c.519dup	p.Val174SerfsTer15	frameshift_variant, splice_region_variant	5/8	1	NM_000133.4	ENSP00000218099	P1
F9	ENST00000394090.2	c.405dup	p.Val136SerfsTer15	frameshift_variant, splice_region_variant	4/7	1		ENSP00000377650
F9	ENST00000643157.1	n.1186dup		splice_region_variant, non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Institute of Basic Medical Sciences, Khyber Medical University, Peshawar

Dec 16, 2016

The variant is associated with Moderate Haemophilia B or Factor IX deficiency -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556006174; hg19: chrX-138630648;