X-154969438-C-T

Position:

• chrX-154969438-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.902G>A​(p.Arg301His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.08

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.

• PM1: In a strand (size 7) in uniprot entity FA8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-154969438-C-T is Pathogenic according to our data. Variant chrX-154969438-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154969438-C-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.902G>A	p.Arg301His	missense_variant	7/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.902G>A	p.Arg301His	missense_variant	7/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000647125.1	c.*778G>A		3_prime_UTR_variant, NMD_transcript_variant	8/14			ENSP00000496062

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2016	The R301H pathogenic variant in the F8 gene has been frequently reported in patients with severe hemophilia A (Higuchi et al., 1991). The R301H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R301H variant is a conservative amino acid substitution. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R301S, R301G, R301C, R301P, R301L) and in nearby residues (L296F, V297M, V297A, V297G, R298T, N299I, H300D, H300L, H300P, A303P, A303E, S304P, L305S) have been reported in the Human Gene Mutation Database in association with hemophilia A (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R301H as a pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2018	The F8 c.902G>A; p.Arg301His variant (rs137852403), also known as R282H for legacy nomenclature, is reported in the literature in patients with severe hemophilia (Casana2008, Factor VIII database). This variant is also reported in the ClinVar database (Variation ID: 10192). This variant is not found in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 301 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this missense variant to be damaging. Based on the above information, we consider this variant to be pathogenic. References: Factor VIII database: http://www.factorviii-db.org Casana P et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica 2008; 93:1091-1094. -

F8-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2024

The F8 c.902G>A variant is predicted to result in the amino acid substitution p.Arg301His. This variant is also described using legacy nomenclature as p.Arg282His, has been reported in many individuals with moderate to severe hemophilia A (Higuchi et al. 1991. PubMed ID: 1908096; F8 Database: http://www.factorviii-db.org/advance_search_results.php). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.85
Sift	Benign	0.11	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.87		Gain of sheet (P = 0.0827);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.97

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: rs137852403; hg19: chrX-154197713; COSMIC: COSV100811370; COSMIC: COSV100811370;