rs387906434

Positions:

• chrX-154999531-TACAA-T

Variant summary

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

The ENST00000360256.9(F8):​c.209_212del​(p.Phe70Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000913 in 1,095,552 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 ENST00000360256.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.57

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-154999531-TACAA-T is Pathogenic according to our data. Variant chrX-154999531-TACAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 10159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154999531-TACAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.209_212del	p.Phe70Ter	frameshift_variant	2/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.209_212del	p.Phe70Ter	frameshift_variant	2/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000423959.5	c.104_107del	p.Phe35Ter	frameshift_variant	2/6	3		ENSP00000409446
F8	ENST00000453950.1	c.191_194del	p.Phe64Ter	frameshift_variant	3/5	3		ENSP00000389153
F8	ENST00000647125.1	c.187_190del	p.Leu63ArgfsTer11	frameshift_variant, stop_lost, NMD_transcript_variant	2/14			ENSP00000496062

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095552 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 361164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	The F8 c.209_212delTTGT; p.Phe70Ter variant (rs387906434), also known as c.208_211delTTTG, is published in the medical literature in numerous individuals with severe hemophilia A (Becker 1996, Habart 2003, Liu 1998, F8 database and references therein). Samples from affected individuals with this variant typically exhibit less than 1% of wildtype clotting activity (Habart 2003, Liu 1998, F8 database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes 4 nucleotides, leads to an immediate stop codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is considered to be pathogenic. References: Link to F8 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The F8 c.209_212del (p.Phe70Ter) variant has been reported in hemizygous state in individuals affected with Hemophilia A (Habart 2003). This variant has been reported to the ClinVar database as Pathogenic. The p.Phe70Ter variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 16, 2024

PM2_moderate, PM6, PS4_moderate, PVS1 -

Computational scores

Source: dbNSFP v4.3

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: rs387906434; hg19: chrX-154227806;