rs137852424

Positions:

• chrX-154953991-G-A
• chrX-154953991-G-C
• chrX-154953991-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4 PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1804C>T (p.Arg602Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 12 and expected to result in nonsense-mediated mRNA decay. This variant is absent from males in gnomAD v2.1.1 and v3.1.1, which meets criteria for PM2_Supporting. More than 25 patients with moderate-severe hemophilia A are reported in the literature and internal laboratory data, meeting criteria for PS4_Very Strong and PP4_Moderate (PMID:29296726, 18387975, 18691168, 16769589, 8639447, 20331761). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255124/MONDO:0010602/071

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 2.16

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 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.1804C>T	p.Arg602*	stop_gained	12/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1804C>T	p.Arg602*	stop_gained	12/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1680C>T		non_coding_transcript_exon_variant	13/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*1680C>T		3_prime_UTR_variant	13/14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000010232 / PMID: 1979502). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 02, 2024	The c.1804C>T (p.Arg602Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 12 and expected to result in nonsense-mediated mRNA decay. This variant is absent from males in gnomAD v2.1.1 and v3.1.1, which meets criteria for PM2_Supporting. More than 25 patients with moderate-severe hemophilia A are reported in the literature and internal laboratory data, meeting criteria for PS4_Very Strong and PP4_Moderate (PMID: 29296726, 18387975, 18691168, 16769589, 8639447, 20331761). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PVS1, PS4_Very Strong, PP4_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2018	The F8 c.1804C>T; p.Arg602Ter variant (rs137852424), also known as R583X, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (Johnsen 2017, Lu 2018, Salviato 2007, F8 database and references therein). This variant is reported in ClinVar (Variation ID: 10232), 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. Functional analyses of the variant protein show a lack of immunofluorescence staining, suggesting degradation of the truncated RNA occurs (Zimmermann 2014). Based on available information, the p.Arg602Ter variant is considered to be pathogenic. References: Link to F8 database: http://www.factorviii-db.org/ Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. Salviato R et al. F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors. Haemophilia. 2007 Jul;13(4):361-72. Zimmermann MA et al. Expression studies of mutant factor VIII alleles with premature termination codons with regard to inhibitor formation. Haemophilia. 2014 May;20(3):e215-21. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.73	D
Vest4		0.91
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs137852424; hg19: chrX-154182266; COSMIC: COSV100811708;