rs17281377

chrX-154838195-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000132.4(F8):c.6901-443G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 111,850 control chromosomes in the GnomAD database, including 248 homozygotes. There are 2,030 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.064 (248 hom., 2030 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6901-443G>A		intron_variant		ENST00000360256.9
F8	NM_019863.3	c.496-443G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6901-443G>A		intron_variant		1	NM_000132.4	P1
F8	ENST00000330287.10	c.496-443G>A		intron_variant		1
F8	ENST00000644698.1	c.634-443G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 7130 AN: 111796 Hom.: 247 Cov.: 22 AF XY: 0.0597 AC XY: 2029 AN XY: 33996

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0234

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.0846

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0757

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0638 AC: 7131 AN: 111850 Hom.: 248 Cov.: 22 AF XY: 0.0596 AC XY: 2030 AN XY: 34060

Gnomad4 AFR AF: 0.0137

Gnomad4 AMR AF: 0.0626

Gnomad4 ASJ AF: 0.0846

Gnomad4 EAS AF: 0.000560

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0710

Gnomad4 NFE AF: 0.0977

Gnomad4 OTH AF: 0.0741

Alfa AF: 0.0896 Hom.: 3625

Bravo AF: 0.0616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	6.1
Dann	Benign	0.86

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: rs17281377; hg19: chrX-154066470;