rs137852382

Positions:

• chrX-154997065-A-G
• chrX-154997065-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_000132.4(F8):​c.296T>C​(p.Val99Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.00

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 8 ACMG points.

• PM1: In a hotspot region, there are 5 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 chrX-154997065-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10165.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant X-154997065-A-G is Pathogenic according to our data. Variant chrX-154997065-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 993612.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.296T>C	p.Val99Ala	missense_variant	3/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.296T>C	p.Val99Ala	missense_variant	3/26	1	NM_000132.4	P1
F8	ENST00000423959.5	c.191T>C	p.Val64Ala	missense_variant	3/6	3
F8	ENST00000453950.1	c.278T>C	p.Val93Ala	missense_variant	4/5	3
F8	ENST00000647125.1	c.*82T>C		3_prime_UTR_variant, NMD_transcript_variant	3/14

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 06, 2019

The F8 c.296T>C; p.Val99Ala variant (rs137852382) is reported in the literature in multiple individuals affected with mild to moderate hemophilia A, including those with F8 activity measured between 5% and 14% of normal (Miller 2012, Factor VIII database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 99 is highly conserved, and other amino acid substitutions at this codon (p.Val99Asp, p.Val99Phe) have been reported in individuals with hemophilia A and are considered disease-causing (Ravanbod 2012, Factor VIII database and references therein). Based on available information, the p.Val99Ala variant is considered to be pathogenic. References: Factor VIII database: http://f8-db.eahad.org Miller CH et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375-82. Ravanbod S et al. Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with haemophilia A. Haemophilia. 2012 May;18(3):e340-6. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.87	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.034	D;T;T
Sift4G	Uncertain	0.019	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.12
MutPred		0.49		Loss of stability (P = 0.0429);.;.;
MVP		0.95
MPC		1.8
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.52
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: rs137852382; hg19: chrX-154225340;