rs137852452

Positions:

• chrX-154903951-G-A
• chrX-154903951-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000132.4(F8):​c.5953C>T​(p.Arg1985*) 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: 22)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.08

Genes affected

F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 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-154903951-G-A is Pathogenic according to our data. Variant chrX-154903951-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10300.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154903951-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.5953C>T	p.Arg1985*	stop_gained	18/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.5953C>T	p.Arg1985*	stop_gained	18/26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 18, 2019	The F8 c.5953C>T; p.Arg1985Ter variant (rs137852452), also known as p.Arg1966Ter in traditional nomenclature, is reported in the literature in multiple individuals affected with severe hemophilia A (see link to Factor VIII database and references therein, Lu 2018, Wang 2010). This variant is reported in ClinVar (Variation ID: 10300), and is absent from general population databases (Exome Variant Server, 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 to be pathogenic. References: Link to Factor VIII Database for p.Arg1985Ter: http://www.factorviii-db.org/advance_search_results.php?dosearch=1&codon=1985 Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. Wang XF et al. The prevalence of factor VIII inhibitors and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia. 2010 Jul 1;16(4):632-9. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.79	D
Vest4		0.94
GERP RS		3.6

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: rs137852452; hg19: chrX-154132226; COSMIC: COSV64272257; COSMIC: COSV64272257;