rs7058826

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.1010-27G>A		intron	N/A	NP_000123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.1010-27G>A		intron	N/A	ENSP00000353393.4
	F8	ENST00000647125.1		n.*886-27G>A		intron	N/A	ENSP00000496062.1
	F8	ENST00000483822.2	TSL:3	n.-198G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.133 AC: 14755 AN: 111001 Hom.: 795 Cov.: 22

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

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

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

GnomAD4 genome AF: 0.133 AC: 14768 AN: 111059 Hom.: 798 Cov.: 22 AF XY: 0.122 AC XY: 4072 AN XY: 33295

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: 17 AN: 216

European-Non Finnish (NFE) AF: 0.151 AC: 7983 AN: 52903

Other (OTH) AF: 0.103 AC: 155 AN: 1511

Alfa AF: 0.143 Hom.: 4846

Bravo AF: 0.133

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary factor VIII deficiency disease (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.1
DANN	Benign	0.65
PhyloP100		0.37
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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