rs387906466

Positions:

• chrX-154837734-CTTGAT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000132.4(F8):​c.6914_6918del​(p.Asn2305ArgfsTer78) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.74

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 Likely_pathogenic. Variant got 7 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 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154837734-CTTGAT-C is Pathogenic according to our data. Variant chrX-154837734-CTTGAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 10331.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154837734-CTTGAT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6914_6918del	p.Asn2305ArgfsTer78	frameshift_variant	26/26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.509_513del	p.Asn170ArgfsTer78	frameshift_variant	5/5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6914_6918del	p.Asn2305ArgfsTer78	frameshift_variant	26/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000330287.10	c.509_513del	p.Asn170ArgfsTer78	frameshift_variant	5/5	1		ENSP00000327895
F8	ENST00000644698.1	c.647_651del	p.Asn216ArgfsTer78	frameshift_variant	6/6			ENSP00000495706

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906466; hg19: chrX-154066009;