chrX-154861759-G-A

Position:

• chrX-154861759-G-A

Variant summary

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

The NM_000132.4(F8):​c.6682C>T​(p.Arg2228Ter) 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: 1.75

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-154861759-G-A is Pathogenic according to our data. Variant chrX-154861759-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10086.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154861759-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.6682C>T	p.Arg2228Ter	stop_gained	24/26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.277C>T	p.Arg93Ter	stop_gained	3/5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6682C>T	p.Arg2228Ter	stop_gained	24/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000330287.10	c.277C>T	p.Arg93Ter	stop_gained	3/5	1		ENSP00000327895
F8	ENST00000644698.1	c.415C>T	p.Arg139Ter	stop_gained	4/6			ENSP00000495706

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000831

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

The F8 c.6682C>T; p.Arg2228Ter variant (rs137852355), also known as Arg2209Ter, is reported in the literature in several individuals with severe hemophilia A (Gitschier 1985, Lyu 2016, see F8 variant database link). This variant is also reported ClinVar (Variation ID: 10086), and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and results in a truncated protein (Zimmermann 2014). Based on available information, this variant is considered to be pathogenic. References: Link to F8 variant database for p.Arg2228Ter: http://www.factorviii-db.org/advance_search_results.php?dosearch=1&nucleotide=6682 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. PMID: 2987704. Lyu C et al. Identification of mutations in the F8 and F9 gene in families with haemophilia using targeted high-throughput sequencing. Haemophilia. 2016 Sep;22(5):e427-34. PMID: 27292088. 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. PMID: 24602271. -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1988

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		3.7

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: rs137852355; hg19: chrX-154090034;