rs1800297

Positions:

chrX-154860563-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The missense variant, NM_000132.3(F8):c.6769A>G (p.Met2257Val), is reported at an MAF of 0.2418 (4578/18936 with 1245 hemizygotes) in the African population in gnomAD v2.1.1. A REVEL score of 0.292 and SpliceAI score of 0 meets BP4 cut-off (respective thresholds <0.3 and <0.05). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency variant curation expert panel for F8: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343869/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.068 ( 621 hom., 2069 hem., cov: 22)

Exomes 𝑓: 0.0073 ( 643 hom. 2076 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 2.30

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 -9 ACMG points.

BP4

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

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.6769A>G	p.Met2257Val	missense_variant	25/26	ENST00000360256.9	NP_000123.1	P00451-1
F8	NM_019863.3 linkuse as main transcript	c.364A>G	p.Met122Val	missense_variant	4/5		NP_063916.1	P00451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.6769A>G	p.Met2257Val	missense_variant	25/26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000330287.10 linkuse as main transcript	c.364A>G	p.Met122Val	missense_variant	4/5	1		ENSP00000327895.6	P00451-2
F8	ENST00000644698.1 linkuse as main transcript	c.502A>G	p.Met168Val	missense_variant	5/6			ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes

AF:

0.0683

AC:

7621

AN:

111642

Hom.:

621

Cov.:

AF XY:

0.0610

AC XY:

2063

AN XY:

33846

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0278

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000564

Gnomad OTH

AF:

0.0520

GnomAD3 exomes

AF:

0.0195

AC:

3579

AN:

183446

Hom.:

323

AF XY:

0.0127

AC XY:

861

AN XY:

67888

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000391

Gnomad OTH exome

AF:

0.00728

GnomAD4 exome

AF:

0.00729

AC:

8006

AN:

1097919

Hom.:

643

Cov.:

AF XY:

0.00571

AC XY:

2076

AN XY:

363277

show subpopulations

Gnomad4 AFR exome

AF:

0.251

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000480

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000211

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0683

AC:

7627

AN:

111697

Hom.:

621

Cov.:

AF XY:

0.0610

AC XY:

2069

AN XY:

33911

show subpopulations

Gnomad4 AFR

AF:

0.237

Gnomad4 AMR

AF:

0.0277

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000374

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000564

Gnomad4 OTH

AF:

0.0513

Alfa

AF:

0.0132

Hom.:

491

Bravo

AF:

0.0778

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.237

AC:

908

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0223

AC:

2704

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 908/10563=8.59% -

Hereditary factor VIII deficiency disease

Benign:3

Benign, no assertion criteria provided	curation	GeneReviews	Sep 22, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Benign, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	Feb 01, 2024	The missense variant, NM_000132.3(F8):c.6769A>G (p.Met2257Val), is reported at an MAF of 0.2418 (4578/18936 with 1245 hemizygotes) in the African population in gnomAD v2.1.1. A REVEL score of 0.292 and SpliceAI score of 0 meets BP4 cut-off (respective thresholds <0.3 and <0.05). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency variant curation expert panel for F8: BA1, BP4. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Uncertain

0.78

.;D;.

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.48

.;N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.081

T;T;.

Sift4G

Benign

0.36

T;T;.

Polyphen

0.24

.;B;.

Vest4

0.052

MPC

0.85

ClinPred

0.012

GERP RS

4.2

Varity_R

0.49

gMVP

0.79

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