NM_000132.4:c.1648C>G

Variant names:

• chrX-154957061-G-C
• rs137852417
• NM_000132.4:c.1648C>G

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.1648C>G​(p.Arg550Gly) variant causes a missense change involving the alteration of a non-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: 2.99

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 domain Plastocyanin-like 3 (size 174) in uniprot entity FA8_HUMAN there are 44 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, 0.995
• PP5: Variant X-154957061-G-C is Pathogenic according to our data. Variant chrX-154957061-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10224.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154957061-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.1648C>G	p.Arg550Gly	missense_variant	Exon 11 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.1648C>G	p.Arg550Gly	missense_variant	Exon 11 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1524C>G		non_coding_transcript_exon_variant	Exon 12 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*1500C>G		3_prime_UTR_variant	Exon 12 of 14			ENSP00000496062.1

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

Oct 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.1648C>G, p.Arg550Gly variant (rs137852417), also known as Arg531Gly, has been reported in two individuals with mild hemophilia A (Higuchi 1991, Tavassoli 1998). Other missense variants at this position (p.Arg550Cys, p.Arg550His, p.Arg550Leu) have also been reported in multiple individuals diagnosed with hemophilia A (Eckhardt 2013). The variant is listed as pathogenic in ClinVar (Variation ID: 10224), and is not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at position 550 is highly conserved, and computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on F8 protein structure or function. Based on the above information, the p.Arg550Gly variant is classified as likely pathogenic. References: Eckhardt C et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013; 122(11):1954-62. Higuchi M et al. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 1991; 88(19):8307-11. Tavassoli K et al. Molecular diagnostics of 15 hemophilia A patients: characterization of eight novel mutations in the factor VIII gene, two of which result in exon skipping. Hum Mutat. 1998; 12(5):301-3. -

Hereditary factor VIII deficiency disease Pathogenic:1

Oct 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.72
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.93		Loss of sheet (P = 0.0315);
MVP		1.0
MPC		1.9
ClinPred		0.96	D
GERP RS		1.9
Varity_R		0.96
gMVP		1.0

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: rs137852417; hg19: chrX-154185336;