rs137852475

Positions:

• chrX-154992945-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000132.4(F8):​c.592T>G​(p.Cys198Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 8.13

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 10 ACMG points.

• PM1: In a disulfide_bond (size 26) in uniprot entity FA8_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-154992945-A-C is Pathogenic according to our data. Variant chrX-154992945-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154992945-A-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.592T>G	p.Cys198Gly	missense_variant	4/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.592T>G	p.Cys198Gly	missense_variant	4/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.487T>G	p.Cys163Gly	missense_variant	4/6	3		ENSP00000409446.1
F8	ENST00000647125.1	n.*378T>G		non_coding_transcript_exon_variant	4/14			ENSP00000496062.1
F8	ENST00000647125.1	n.*378T>G		3_prime_UTR_variant	4/14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2020	The F8 c.592T>G; p.Cys198Gly variant (rs137852475), also known as Cys179Gly, is reported in the literature in several individuals affected with severe hemophilia A (Bogdanova 2005, Markoff 2009, Margaglione 2008, Mazurier 2002, Rydz 2013). This variant is reported in ClinVar (Variation ID: 10351), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 198 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Arg, Tyr, Ser) have been reported in individuals with hemophilia A (Elmahmoudi 2012, Lu 2018, Rydz 2013). Based on available information, the p.Cys198Gly variant is considered to be likely pathogenic. References: Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005;26(3):249-254. Elmahmoudi H et al. First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations. Diagn Pathol. 2012;7:93. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018;24(2):291-298. Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93(5):722-728. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009;15(4):932-941. Mazurier C et al. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Br J Haematol. 2002;119(2):390-392. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013;88(12):1030-1034. References: Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005;26(3):249-254. Elmahmoudi H et al. First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations. Diagn Pathol. 2012;7:93. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018;24(2):291-298. Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93(5):722-728. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009;15(4):932-941. Mazurier C et al. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Br J Haematol. 2002;119(2):390-392. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013;88(12):1030-1034. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.87		Gain of disorder (P = 0.0063);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs137852475; hg19: chrX-154221220;