rs782654096

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 1.96

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hemophilia A
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
mild hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
moderately severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of hemophilia A in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.6724G>A	p.Val2242Met	missense_variant, splice_region_variant	Exon 25 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3 link	c.319G>A	p.Val107Met	missense_variant, splice_region_variant	Exon 4 of 5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
F8	ENST00000360256.9 link	c.6724G>A	p.Val2242Met	missense_variant, splice_region_variant	Exon 25 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10 link	c.319G>A	p.Val107Met	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1 link	c.457G>A	p.Val153Met	missense_variant, splice_region_variant	Exon 5 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112010

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000518

AC:

AN:

183419

AF XY:

0.000427

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 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

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00573

AC:

173

AN:

30200

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4091

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841474

Other (OTH)

AF:

0.000282

AC:

AN:

46064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000116

AC:

AN:

112061

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34229

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30891

American (AMR)

AF:

0.00

AC:

AN:

10544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00366

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53233

Other (OTH)

AF:

0.00

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000428

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Uncertain:1Benign:2

Oct 16, 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. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Oct 11, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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. -

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

(source)

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;.

PhyloP100

2.0

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

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over