rs137852356

Positions:

• chrX-154896103-G-A
• chrX-154896103-G-C
• chrX-154896103-G-T

Variant summary

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

The NM_000132.4(F8):​c.6403C>T​(p.Arg2135*) 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, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.51

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 18 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-154896103-G-A is Pathogenic according to our data. Variant chrX-154896103-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154896103-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.6403C>T	p.Arg2135*	stop_gained	22/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6403C>T	p.Arg2135*	stop_gained	22/26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2021	PM2, PS4_Moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 24602271, 20331753, 3097553, 33706050, 29381227, 32897612, 35014236, 29296726) -

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2021	The F8 c.6403C>T; p.Arg2135Ter variant (rs137852356), also known as Arg2116Ter, has been reported in multiple patients diagnosed with severe hemophilia A (see link to Factor VIII database, Higuchi 1989, Jayandharan 2009, Millar 1991, Tavasolli 1997, Wang 2010, Yousouffian 1986). This variant is also reported in ClinVar (Variation ID: 10088), but is absent from the 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: Factor VIII variant database: http://www.factorviii-db.org/advance_search_results.php?dosearch=1&codon=2135 Higuchi M et al. Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis. Blood. 1989 Aug 15;74(3):1045-51. PMID: 2473810. Jayandharan G et al.Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. PMID: 19686262. Millar D et al. The molecular genetics of haemophilia A: screening for point mutations in the factor VIII gene using the restriction enzyme TaqI. Hum Genet. 1991 Sep;87(5):607-12. PMID: 1840568. Tavassoli K et al. Mutational analysis of ectopic factor VIII transcripts from hemophilia A patients: identification of cryptic splice site, exon skipping and novel point mutations. Hum Genet. 1997 Oct;100(5-6):508-11. PMID: 9341862. Wang X 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. PMID: 20331753. Youssoufian H et al. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature. 1986 Nov 27-Dec 3;324(6095):380-2. PMID: 3097553. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 27, 1986	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.90
GERP RS		-0.042

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137852356; hg19: chrX-154124378; COSMIC: COSV64277148; COSMIC: COSV64277148;