rs782654096

Positions:

chrX-154860608-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.6724G>A variant in F8 is a missense variant predicted to cause substitution of Valine by Methionine at amino acid 2242 (p.Val2242Met), affecting the first nucleotide in exon 25. The c.6724G>A (p.Val2242Met) variant is reported at an MAF of 0.006735 (100/14847 alleles) in the East Asian population in gnomAD v2.1.1, with 32 hemizygotes, meeting BA1 criteria of MAF >= 0.000333. In summary, this variant is classified as a Benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10567761/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 75 hem. )

Consequence

F8
NM_000132.4 missense, splice_region

Scores

Splicing: ADA: 0.9979

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.96

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 Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.6724G>A	p.Val2242Met	missense_variant, splice_region_variant	25/26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3 linkuse as main transcript	c.319G>A	p.Val107Met	missense_variant, splice_region_variant	4/5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.6724G>A	p.Val2242Met	missense_variant, splice_region_variant	25/26	1	NM_000132.4	ENSP00000353393	P1	P00451-1
F8	ENST00000330287.10 linkuse as main transcript	c.319G>A	p.Val107Met	missense_variant, splice_region_variant	4/5	1		ENSP00000327895		P00451-2
F8	ENST00000644698.1 linkuse as main transcript	c.457G>A	p.Val153Met	missense_variant, splice_region_variant	5/6			ENSP00000495706

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112010

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34168

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00365

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000518

AC:

AN:

183419

Hom.:

AF XY:

0.000427

AC XY:

AN XY:

67867

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00678

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

188

AN:

1097447

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

362847

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00573

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000116

AC:

AN:

112061

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34229

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00366

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000428

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 16, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0087

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

0.80

D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N;.

REVEL

Uncertain

0.64

Sift

Benign

0.23

T;D;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.99

.;D;.

Vest4

0.14

MutPred

0.78

.;Gain of disorder (P = 0.0654);.;

MVP

0.98

MPC

1.7

ClinPred

0.17

GERP RS

5.3

Varity_R

0.45

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

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