X-154837685-C-G

Position:

• chrX-154837685-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000132.4(F8):​c.6968G>C​(p.Arg2323Pro) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2323G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.63

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 11 ACMG points.

• PM1: In a domain F5/8 type C 2 (size 152) in uniprot entity FA8_HUMAN there are 31 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, 0.992
• PP5: Variant X-154837685-C-G is Pathogenic according to our data. Variant chrX-154837685-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1684377.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6968G>C	p.Arg2323Pro	missense_variant	26/26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.563G>C	p.Arg188Pro	missense_variant	5/5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6968G>C	p.Arg2323Pro	missense_variant	26/26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.563G>C	p.Arg188Pro	missense_variant	5/5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.701G>C	p.Arg234Pro	missense_variant	6/6			ENSP00000495706.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.70
CADD	Benign	23
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	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.2	.;H;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.5	D;D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.71
MutPred		0.94		.;Loss of methylation at R2323 (P = 0.0778);.;
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.99
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: rs137852474; hg19: chrX-154065960;