rs137852459

Positions:

• chrX-154896135-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.6371A>G​(p.Tyr2124Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,095,316 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.96

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 16 ACMG points.

• PM1: In a disulfide_bond (size 148) in uniprot entity FA8_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-154896135-T-C is Pathogenic according to our data. Variant chrX-154896135-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154896135-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6371A>G	p.Tyr2124Cys	missense_variant	22/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6371A>G	p.Tyr2124Cys	missense_variant	22/26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183296 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000633

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095316 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 360772

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: 0.0000494

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.000110

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2024	Variant summary: F8 c.6371A>G (p.Tyr2124Cys) results in a non-conservative amino acid change located in the Coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183296 control chromosomes. c.6371A>G has been reported in the literature in multiple individuals affected with milder/non-severe Factor VIII Deficiency (Hemophilia A). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10310). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2021	The F8 6371A>G; p.Tyr2124Cys variant (rs137852459), also known as Tyr2105Cys, has been described in the literature in numerous individuals with mild/moderate hemophilia A (Naylor 1993, Margaglione 2008, Johnsen 2017, Williams 2015, F8 database), and it is also reported in ClinVar (Variation ID: 10310). This variant is only observed on one allele (one hemizygote) in the Genome Aggregation Database, indicating it is not a common polymorphism. The tyrosine at codon 2124 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.97). Taken together, this variant is considered pathogenic. References: Naylor JA et al. Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients. Hum Mol Genet. 1993 Jan;2(1):11-7. PMID: 8490618 Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008 May;93(5):722-8. PMID: 18387975 Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. PMID: 29296726 Williams VK et al. Extensive bleeding due to an inhibitor in a haemophilia A patient with a Tyr2105Cys mutation: elimination of the inhibitor with rituximab. Pathology. 2015 Oct;47(6):586-8. PMID: 26308136 Link to F8 database: https://f8-db.eahad.org/VariantPage.php?ID=1594&hash=2a3f84a96bdd139de9f11adfe4865fbc -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 10, 2023	The F8 c.6371A>G variant is classified as Likely Pathogenic (PS4_Moderate, PM1, PM2, PP3) The F8 c.6371A>G variant is a single nucleotide change in exon 22/26 of the F8 gene, which is predicted to change the amino acid tyrosine at position 2124 in the protein to cysteine. The variant has been reported in numerous individuals with a clinical presentation of mild to severe haemophilia as reported in the EAHAD F8 Variant database (PS4_Mod). Note that this variant is also reported in the literature as Tyr2105Cys.This variant is absent from population databases (PM2). This variant is located in the Factor VIII C domain which contains key binding sites for von Willebrand factor (vWF) and phospholipid membranes (PMID: 10910913) (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852459) and in the HGMD database: CM930235. It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10310). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 23, 2020

PP3, PM2, PS4_moderate, PP1_strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.91		Gain of ubiquitination at K2129 (P = 0.1295);
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
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: rs137852459; hg19: chrX-154124410;