rs1800292

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.3864A>C (p.Ser1288=) variant is reported at an MAF of 0.3377 (6437/19059 alleles) in the South Asian population in gnomAD v2.1.,1 with 3958 hemizygotes and 424 homozygotes, meeting BA1 criteria of MAF > 0.000333. The synonymous variant is predicted to have no impact on splicing based on SpliceAI score of 0.0, meeting BP4. 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/F9: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343867/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.10 ( 553 hom., 3346 hem., cov: 22)

Exomes 𝑓: 0.11 ( 5194 hom. 41809 hem. )

Consequence

F8
NM_000132.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.915

Publications

8 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 -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 rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.3864A>C	p.Ser1288Ser	synonymous_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 link	c.3864A>C	p.Ser1288Ser	synonymous_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1 link	n.*3530A>C		downstream_gene_variant				ENSP00000496062.1

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

11138

AN:

111284

Hom.:

555

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0677

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.350

Gnomad FIN

AF:

0.0506

Gnomad MID

AF:

0.159

Gnomad NFE

AF:

0.0844

Gnomad OTH

AF:

0.131

GnomAD2 exomes

AF:

0.147

AC:

26861

AN:

182684

AF XY:

0.155

show subpopulations

Gnomad AFR exome

AF:

0.0669

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.0578

Gnomad NFE exome

AF:

0.0886

Gnomad OTH exome

AF:

0.146

GnomAD4 exome

AF:

0.106

AC:

116489

AN:

1097891

Hom.:

5194

Cov.:

AF XY:

0.115

AC XY:

41809

AN XY:

363287

show subpopulations

African (AFR)

AF:

0.0645

AC:

1703

AN:

26394

American (AMR)

AF:

0.252

AC:

8857

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

3396

AN:

19382

East Asian (EAS)

AF:

0.117

AC:

3519

AN:

30203

South Asian (SAS)

AF:

0.340

AC:

18410

AN:

54131

European-Finnish (FIN)

AF:

0.0612

AC:

2470

AN:

40386

Middle Eastern (MID)

AF:

0.233

AC:

962

AN:

4136

European-Non Finnish (NFE)

AF:

0.0845

AC:

71175

AN:

841993

Other (OTH)

AF:

0.130

AC:

5997

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

4144

8289

12433

16578

20722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2914

5828

8742

11656

14570

<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:

0.0999

AC:

11128

AN:

111341

Hom.:

553

Cov.:

AF XY:

0.0997

AC XY:

3346

AN XY:

33577

show subpopulations

African (AFR)

AF:

0.0676

AC:

2076

AN:

30726

American (AMR)

AF:

0.193

AC:

2009

AN:

10416

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

476

AN:

2637

East Asian (EAS)

AF:

0.163

AC:

572

AN:

3518

South Asian (SAS)

AF:

0.347

AC:

903

AN:

2600

European-Finnish (FIN)

AF:

0.0506

AC:

306

AN:

6050

Middle Eastern (MID)

AF:

0.151

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0845

AC:

4474

AN:

52969

Other (OTH)

AF:

0.130

AC:

199

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

349

698

1047

1396

1745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0993

Hom.:

4037

Bravo

AF:

0.108

EpiCase

AF:

0.0980

EpiControl

AF:

0.0931

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary factor VIII deficiency disease

Benign:3

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.

Feb 01, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.3864A>C (p.Ser1288=) variant is reported at an MAF of 0.3377 (6437/19059 alleles) in the South Asian population in gnomAD v2.1.,1 with 3958 hemizygotes and 424 homozygotes, meeting BA1 criteria of MAF > 0.000333. The synonymous variant is predicted to have no impact on splicing based on SpliceAI score of 0.0, meeting BP4. 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/F9: BA1, BP4.

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.1

(source)

DANN

Benign

0.59

PhyloP100

0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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