rs137852422

Positions:

• chrX-154956959-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000132.4(F8):​c.1750C>A​(p.Gln584Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q584H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense, splice_region
• Scores: Splicing: ADA: 0.4710
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.34

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant X-154956959-G-T is Pathogenic according to our data. Variant chrX-154956959-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10230.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154956959-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.1750C>A	p.Gln584Lys	missense_variant, splice_region_variant	11/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.1750C>A	p.Gln584Lys	missense_variant, splice_region_variant	11/26	1	NM_000132.4	P1
F8	ENST00000647125.1	c.*1626C>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	12/14

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.80		Gain of methylation at Q584 (P = 0.0098);
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Pathogenic	0.72
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: rs137852422; hg19: chrX-154185234;