X-154837686-G-C

Position:

• chrX-154837686-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000132.4(F8):​c.6967C>G​(p.Arg2323Gly) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2323H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.47

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 14 ACMG points.

• PS1: Transcript NM_000132.4 (F8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chrX-154837686-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-154837686-G-C is Pathogenic according to our data. Variant chrX-154837686-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 618642.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154837686-G-C is described in Lovd as [Likely_pathogenic]. Variant chrX-154837686-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6967C>G	p.Arg2323Gly	missense_variant	26/26	ENST00000360256.9
F8	NM_019863.3	c.562C>G	p.Arg188Gly	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6967C>G	p.Arg2323Gly	missense_variant	26/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.562C>G	p.Arg188Gly	missense_variant	5/5	1
F8	ENST00000644698.1	c.700C>G	p.Arg234Gly	missense_variant	6/6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

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

May 20, 2018

The F8 c.6967C>G; p.Arg2323Gly variant (rs137852473), also reported as Arg2304Gly, is reported in the medical literature in at least one individual with hemophilia A (Liu 2000). Additionally, other variants in the same codon, p.Arg2323Cys, p.Arg2323His, p.Arg2323Leu, p.Arg2323Pro, are also described in individuals with hemophilia A (Eckhardt 2013, Liu 2000, Schwaab 1995, Timur 2001). The p.Arg2323Gly variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2323 is highly conserved across species and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Eckhardt CL et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013 Sep 12;122(11):1954-62. Liu ML et al. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood. 2000 Aug 1;96(3):979-87. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. Timur AA et al. Molecular pathology of haemophilia A in Turkish patients: identification of 36 independent mutations. Haemophilia. 2001 Sep;7(5):475-81. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.9	.;H;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.5	D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.72
MutPred		0.99		.;Loss of stability (P = 0.0466);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.98
gMVP		0.99

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: rs137852473; hg19: chrX-154065961;