rs137852354

chrX-154837677-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000132.4(F8):c.6976C>T(p.Arg2326Ter) 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 (★★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.209

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154837677-G-A is Pathogenic according to our data. Variant chrX-154837677-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10085.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-154837677-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6976C>T	p.Arg2326Ter	stop_gained	26/26	ENST00000360256.9
F8	NM_019863.3	c.571C>T	p.Arg191Ter	stop_gained	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6976C>T	p.Arg2326Ter	stop_gained	26/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.571C>T	p.Arg191Ter	stop_gained	5/5	1
F8	ENST00000644698.1	c.709C>T	p.Arg237Ter	stop_gained	6/6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 20, 2020	PVS1, PM2, PP4, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 08, 2021	The F8 c.6976C>T; p.Arg2326Ter variant (rs137852354), also known as p.Arg2307Ter, is reported in the literature in numerous individuals affected with severe hemophilia A and several individuals with mild-to-moderate hemophilia (Becker 1996, Gitschier 1985, Higuchi 1989, Higuchi 1991, Hill 2005, Hua 2010, Jayandharan 2009, Levinson 1990, Millar 1991, Nair 2016, Factor VIII database). The p.Arg2326Ter variant cosegregates with affected individuals in at least one family (Gitschier 1985) and has been reported as a de novo variant in another case (Levinson 1990). This variant is reported in ClinVar (Variation ID: 10085) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the F8 gene. While this may not lead to nonsense-mediated decay, it is predicted to produce a truncated protein lacking 26 amino acids, many of which exhibit pathogenic missense variants and thus are likely to be functionally important. Based on available information, the p.Arg2326Ter variant is considered to be pathogenic. References: Factor VIII database: http://www.factorviii-db.org/ Becker J et al. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet. 1996 Apr;58(4):657-70. Gitschier J et al. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature. 1985 May 30-Jun 5;315(6018):427-30. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. 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. Hill M et al. Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. Haemophilia. 2005 Mar;11(2):133-41. Hua BL et al. Identification of seven novel mutations in the factor VIII gene in 18 unrelated Chinese patients with hemophilia A. Chin Med J (Engl). 2010 Feb 5;123(3):305-10. Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Levinson B et al. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990 Jan;46(1):53-62. Millar DS 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. Nair PS et al. Factor VIII Antigen, Activity, and Mutations in Hemophilia A. Clin Appl Thromb Hemost. 2016 May;22(4):381-5. -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 02, 2024	The c.6976C>T (p.Arg2326Ter) creates a premature stop codon in exon 26, which is the last exon of the F8 gene. Therefore, protein is not expected to undergo NMD and meets PVS1_Strong. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. More than 20 patients are reported in the literature with severe/moderate hemophilia A, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate. The variant was also reported in two affected brothers and their carrier mother, which meets criteria for PP1 (PMID: 2987704). There is also at least one report of a de novo case where maternity was not confirmed, meeting PS2_Moderate (PMID: 2104741). 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 F9: PVS1_Strong, PS4_Very strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	25
Dann	Benign	0.96
FATHMM_MKL	Benign	0.018	N
MutationTaster	Benign	1.0	D;D
Vest4		0.74
GERP RS		-3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137852354; hg19: chrX-154065952; COSMIC: COSV57704724; COSMIC: COSV57704724;