rs7058826

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000132.4(F8):c.1010-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,204,928 control chromosomes in the GnomAD database, including 9,109 homozygotes. There are 54,452 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.13 ( 798 hom., 4072 hem., cov: 22)

Exomes 𝑓: 0.14 ( 8311 hom. 50380 hem. )

Consequence

F8
NM_000132.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.372

Publications

9 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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-154966714-C-T is Benign according to our data. Variant chrX-154966714-C-T is described in ClinVar as [Benign]. Clinvar id is 439674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.1010-27G>A		intron_variant	Intron 7 of 25	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.1010-27G>A	intron_variant	Intron 7 of 25	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*886-27G>A	intron_variant	Intron 8 of 13			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000483822.2 link	n.-198G>A	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

14755

AN:

111001

Hom.:

795

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.0971

Gnomad ASJ

AF:

0.0870

Gnomad EAS

AF:

0.0506

Gnomad SAS

AF:

0.0455

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.0763

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.123

AC:

22205

AN:

180431

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.0723

Gnomad EAS exome

AF:

0.0479

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.145

AC:

158283

AN:

1093869

Hom.:

8311

Cov.:

AF XY:

0.140

AC XY:

50380

AN XY:

360243

show subpopulations

African (AFR)

AF:

0.136

AC:

3590

AN:

26349

American (AMR)

AF:

0.139

AC:

4888

AN:

35143

Ashkenazi Jewish (ASJ)

AF:

0.0749

AC:

1450

AN:

19368

East Asian (EAS)

AF:

0.0745

AC:

2249

AN:

30193

South Asian (SAS)

AF:

0.0499

AC:

2698

AN:

54077

European-Finnish (FIN)

AF:

0.147

AC:

5684

AN:

38796

Middle Eastern (MID)

AF:

0.0751

AC:

310

AN:

4130

European-Non Finnish (NFE)

AF:

0.157

AC:

131532

AN:

839808

Other (OTH)

AF:

0.128

AC:

5882

AN:

46005

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

4472

8944

13417

17889

22361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.133

AC:

14768

AN:

111059

Hom.:

798

Cov.:

AF XY:

0.122

AC XY:

4072

AN XY:

33295

show subpopulations

African (AFR)

AF:

0.137

AC:

4188

AN:

30573

American (AMR)

AF:

0.0974

AC:

1021

AN:

10485

Ashkenazi Jewish (ASJ)

AF:

0.0870

AC:

228

AN:

2622

East Asian (EAS)

AF:

0.0508

AC:

180

AN:

3545

South Asian (SAS)

AF:

0.0463

AC:

121

AN:

2611

European-Finnish (FIN)

AF:

0.133

AC:

788

AN:

5918

Middle Eastern (MID)

AF:

0.0787

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.151

AC:

7983

AN:

52903

Other (OTH)

AF:

0.103

AC:

155

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

464

928

1393

1857

2321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.143

Hom.:

4846

Bravo

AF:

0.133

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2021

GeneDx

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

- -

Hereditary factor VIII deficiency disease

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

-0.87

CADD

Benign

7.1

(source)

DANN

Benign

0.65

PhyloP100

0.37

BranchPoint Hunter

4.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs7058826

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