rs137852357

Positions:

• chrX-154863161-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.6496C>T​(p.Arg2166Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000913 in 1,095,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.94

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-154863161-G-A is Pathogenic according to our data. Variant chrX-154863161-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10096.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154863161-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.6496C>T	p.Arg2166Ter	stop_gained	23/26	ENST00000360256.9
F8	NM_019863.3	c.91C>T	p.Arg31Ter	stop_gained	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6496C>T	p.Arg2166Ter	stop_gained	23/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.91C>T	p.Arg31Ter	stop_gained	2/5	1
F8	ENST00000644698.1	c.229C>T	p.Arg77Ter	stop_gained	3/6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095245 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360657

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.000147

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 04, 2021	The F8 c.6496C>T; p.Arg2166Ter variant (rs137852357), also known as Arg2147Ter, is reported in the literature in several individuals affected with severe hemophilia A (see link to FVIII database and references therein, Feng 2021, Kang 2021, Villarreal-Martinez 2020). This variant is also reported in ClinVar (Variation ID: 10096), 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: Link to FVIII database: https://f8-db.eahad.org Feng Y et al. Mutation analysis in the F8 gene in 485 families with haemophilia A and prenatal diagnosis in China. Haemophilia. 2021 Jan;27(1):e88-e92PMID: 33245802. Kang H et al. FVIII inhibitor risk correlated with F8 gene variants in 296 unrelated male Chinese patients with haemophilia A. Haemophilia. 2021 Mar;27(2):e274-e277. PMID: 32897612. Villarreal-Martinez L et al. Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants. Blood Cells Mol Dis. 2020 Jul;83:102423. PMID: 32224444. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1988	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.70	D
MutationTaster	Benign	1.0	A;A
Vest4		0.91
GERP RS		3.9

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: rs137852357; hg19: chrX-154091436; COSMIC: COSV57704509;