Variant rs7058826 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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 -20 ACMG points.

BP4

This place is a probable branch point but rather VUS (scored 4 / 10). 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. Variant chrX-154966714-C-T is described in Lovd as [Likely_pathogenic].

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/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.1010-27G>A		intron_variant		ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.1010-27G>A		intron_variant		1	NM_000132.4	ENSP00000353393	P1	P00451-1
F8	ENST00000647125.1 linkuse as main transcript	c.*886-27G>A		intron_variant, NMD_transcript_variant				ENSP00000496062

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

14755

AN:

111001

Hom.:

795

Cov.:

AF XY:

0.122

AC XY:

4064

AN XY:

33227

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

GnomAD3 exomes

AF:

0.123

AC:

22205

AN:

180431

Hom.:

1143

AF XY:

0.114

AC XY:

7474

AN XY:

65571

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 SAS exome

AF:

0.0502

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

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.0749

Gnomad4 EAS exome

AF:

0.0745

Gnomad4 SAS exome

AF:

0.0499

Gnomad4 FIN exome

AF:

0.147

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.128

GnomAD4 genome

AF:

0.133

AC:

14768

AN:

111059

Hom.:

798

Cov.:

AF XY:

0.122

AC XY:

4072

AN XY:

33295

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.0974

Gnomad4 ASJ

AF:

0.0870

Gnomad4 EAS

AF:

0.0508

Gnomad4 SAS

AF:

0.0463

Gnomad4 FIN

AF:

0.133

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.141

Hom.:

3419

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Hereditary factor VIII deficiency disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.1

DANN

Benign

0.65

BranchPoint Hunter

4.0

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