rs137852459

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.96

Variant links:

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]

F8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain F5/8 type C 1 (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 rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.6371A>G	p.Tyr2124Cys	missense_variant	Exon 22 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 link	c.6371A>G	p.Tyr2124Cys	missense_variant	Exon 22 of 26	1	NM_000132.4	ENSP00000353393.4		P00451-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183296

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67736

show subpopulations

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:

AN:

1095316

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360772

show subpopulations

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.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:3

Feb 10, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:2

Dec 23, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PS4_moderate, PP1_strong -

Jan 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.6371A>G; p.Tyr2124Cys variant (rs137852459), also known as Tyr2105Cys, has been described in the literature in numerous individuals with mild or moderate hemophilia A (Naylor 1993, Margaglione 2008, Johnsen 2017, Williams 2015, F8 database). This variant is also reported in ClinVar (Variation ID: 10310), but is only observed on one allele (one hemizygote) in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.970). Based on available information, this variant is considered pathogenic. References: Link to F8 database: https://f8-db.eahad.org/VariantPage.php?ID=1594&hash=2a3f84a96bdd139de9f11adfe4865fbc 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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.74

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.97

MutPred

0.91

Gain of ubiquitination at K2129 (P = 0.1295);

MVP

1.0

MPC

2.1

ClinPred

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over