rs28933668

Positions:

• chrX-154966522-G-A
• chrX-154966522-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000132.4(F8):​c.1175C>T​(p.Ser392Leu) variant causes a missense change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.85

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]

F8 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-154966522-G-A is Pathogenic according to our data. Variant chrX-154966522-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10205.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154966522-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.1175C>T	p.Ser392Leu	missense_variant	8/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1175C>T	p.Ser392Leu	missense_variant	8/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1051C>T		non_coding_transcript_exon_variant	9/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*1051C>T		3_prime_UTR_variant	9/14			ENSP00000496062.1
F8	ENST00000483822.2	n.-6C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 14, 2022

The F8 c.1175C>T; p.Ser392Leu variant (rs28933668), also known as p.Ser373Leu, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see F8 database and references therein). Functional analyses demonstrate that individuals with this variant have factor VIII activity between 8-9% (F8 database). This variant is also reported in ClinVar (Variation ID: 10205) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1174T>C, p.Ser392Pro) has been reported in individuals with mild hemophilia A and is considered pathogenic (Schwaab 1997). The serine at codon 392 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.82). Based on available information, this variant is considered to be likely pathogenic. References: Link to F8 database: https://f8-db.eahad.org/ Schwaab R et al. Factor VIII gene mutations found by a comparative study of SSCP, DGGE and CMC and their analysis on a molecular model of factor VIII protein. Hum Genet. 1997 Dec;101(3):323-32. PMID: 9439662. -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.84		Loss of methylation at K396 (P = 0.0554);
MVP		0.98
MPC		1.5
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.44
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs28933668; hg19: chrX-154194797;