rs7058826

Variant names:

• chrX-154966714-C-T
• rs7058826
• NM_000132.4:c.1010-27G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.372

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]

ACMG classification

Verdict is Benign. Variant got -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. 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 rank	MANE	Protein	UniProt
F8	NM_000132.4	c.1010-27G>A		intron_variant	Intron 7 of 25	ENST00000360256.9	NP_000123.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14755 AN: 111001 Hom.: 795 Cov.: 22 AF XY: 0.122 AC XY: 4064 AN XY: 33227

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

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.: 30 AF XY: 0.140 AC XY: 50380 AN XY: 360243

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.: 22 AF XY: 0.122 AC XY: 4072 AN XY: 33295

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

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
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

Other links and lift over

dbSNP: rs7058826; hg19: chrX-154194989; COSMIC: COSV64273834; COSMIC: COSV64273834;