X-154930010-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000132.4(F8):c.3780C>G(p.Asp1260Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,207,733 control chromosomes in the GnomAD database, including 20,423 homozygotes. There are 70,527 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 5548 hom., 9023 hem., cov: 22)

Exomes 𝑓: 0.18 ( 14875 hom. 61504 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.400

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.852606E-6).

BP6

Variant X-154930010-G-C is Benign according to our data. Variant chrX-154930010-G-C is described in ClinVar as [Benign]. Clinvar id is 40999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154930010-G-C is described in Lovd as [Likely_pathogenic]. Variant chrX-154930010-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.3780C>G	p.Asp1260Glu	missense_variant	Exon 14 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.3780C>G	p.Asp1260Glu	missense_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4		P00451-1
F8	ENST00000647125.1 link	n.*3446C>G		downstream_gene_variant				ENSP00000496062.1		A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

32725

AN:

110565

Hom.:

5547

Cov.:

AF XY:

0.274

AC XY:

8989

AN XY:

32825

show subpopulations

Gnomad AFR

AF:

0.648

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.0517

Gnomad SAS

AF:

0.0505

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.258

GnomAD3 exomes

AF:

0.184

AC:

33480

AN:

182390

Hom.:

3687

AF XY:

0.161

AC XY:

10775

AN XY:

67066

show subpopulations

Gnomad AFR exome

AF:

0.664

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.0481

Gnomad SAS exome

AF:

0.0547

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.178

AC:

194786

AN:

1097115

Hom.:

14875

Cov.:

AF XY:

0.170

AC XY:

61504

AN XY:

362629

show subpopulations

Gnomad4 AFR exome

AF:

0.661

Gnomad4 AMR exome

AF:

0.182

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.0745

Gnomad4 SAS exome

AF:

0.0548

Gnomad4 FIN exome

AF:

0.168

Gnomad4 NFE exome

AF:

0.175

Gnomad4 OTH exome

AF:

0.186

GnomAD4 genome

AF:

0.296

AC:

32765

AN:

110618

Hom.:

5548

Cov.:

AF XY:

0.274

AC XY:

9023

AN XY:

32888

show subpopulations

Gnomad4 AFR

AF:

0.648

Gnomad4 AMR

AF:

0.181

Gnomad4 ASJ

AF:

0.156

Gnomad4 EAS

AF:

0.0518

Gnomad4 SAS

AF:

0.0507

Gnomad4 FIN

AF:

0.155

Gnomad4 NFE

AF:

0.172

Gnomad4 OTH

AF:

0.254

Alfa

AF:

0.159

Hom.:

3943

Bravo

AF:

0.316

TwinsUK

AF:

0.174

AC:

647

ALSPAC

AF:

0.169

AC:

487

ESP6500AA

AF:

0.650

AC:

2492

ESP6500EA

AF:

0.174

AC:

1168

ExAC

AF:

0.184

AC:

22360

EpiCase

AF:

0.164

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33245802, 30792900, 26105150, 15735794, 24108539, 24086941, 17209060, 20054547) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor VIII deficiency disease

Benign:2Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.037

DANN

Benign

0.11

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.00082

LIST_S2

Benign

0.15

MetaRNN

Benign

0.0000069

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

0.94

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.0070

MutPred

0.096

Gain of disorder (P = 0.1105);

MPC

0.044

ClinPred

0.00047

GERP RS

0.78

Varity_R

0.037

gMVP

0.19

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