rs1800292

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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:

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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 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	P00451-1

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		P00451-1
F8	ENST00000647125.1 link	n.*3530A>C		downstream_gene_variant				ENSP00000496062.1		A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

11138

AN:

111284

Hom.:

555

Cov.:

AF XY:

0.0998

AC XY:

3343

AN XY:

33510

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

GnomAD3 exomes

AF:

0.147

AC:

26861

AN:

182684

Hom.:

1653

AF XY:

0.155

AC XY:

10429

AN XY:

67466

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 SAS exome

AF:

0.338

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

Gnomad4 AFR exome

AF:

0.0645

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.175

Gnomad4 EAS exome

AF:

0.117

Gnomad4 SAS exome

AF:

0.340

Gnomad4 FIN exome

AF:

0.0612

Gnomad4 NFE exome

AF:

0.0845

Gnomad4 OTH exome

AF:

0.130

GnomAD4 genome

AF:

0.0999

AC:

11128

AN:

111341

Hom.:

553

Cov.:

AF XY:

0.0997

AC XY:

3346

AN XY:

33577

show subpopulations

Gnomad4 AFR

AF:

0.0676

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.163

Gnomad4 SAS

AF:

0.347

Gnomad4 FIN

AF:

0.0506

Gnomad4 NFE

AF:

0.0845

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.0975

Hom.:

2697

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor VIII deficiency disease

Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.1

DANN

Benign

0.59

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