rs137852472

Positions:

• chrX-154837697-G-A
• chrX-154837697-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.6956C>T​(p.Pro2319Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,451 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2319S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.96

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 18 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 chrX-154837698-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10147.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-154837697-G-A is Pathogenic according to our data. Variant chrX-154837697-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154837697-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154837697-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6956C>T	p.Pro2319Leu	missense_variant	26/26	ENST00000360256.9
F8	NM_019863.3	c.551C>T	p.Pro184Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6956C>T	p.Pro2319Leu	missense_variant	26/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.551C>T	p.Pro184Leu	missense_variant	5/5	1
F8	ENST00000644698.1	c.689C>T	p.Pro230Leu	missense_variant	6/6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097451 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362813

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000907

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2023	The F8 c.6956C>T; p.Pro2319Leu variant (rs137852472), also known as Pro2300Leu in traditional nomenclature, is reported in the literature in numerous individuals affected with mild-to-moderate hemophilia A (Higuchi 1991, see link to F8 database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 2319 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.874). Additionally, other variants at this codon (c.6955C>T, p.Pro2319Ser; c.6956C>G, p.Pro2319Arg) have been reported in individuals with hemophilia A and are considered disease-causing (see link to F8 database). Based on available information, the p.Pro2319Leu variant is considered to be pathogenic. References: Link to F8 database: https://f8-db.eahad.org/ 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 Oct 1;88(19):8307-11. PMID: 1924291. -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Hereditary factor VIII deficiency disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-9.3	D;D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.71
MutPred		0.94		.;Loss of catalytic residue at P2318 (P = 0.0564);.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.92
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: rs137852472; hg19: chrX-154065972;