X-154945255-G-T

Position:

• chrX-154945255-G-T

Variant summary

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

The NM_000132.4(F8):​c.2113+2443C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 109,504 control chromosomes in the GnomAD database, including 13,306 homozygotes. There are 17,413 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 0.54 (13306 hom., 17413 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.2113+2443C>A		intron_variant		ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.2113+2443C>A		intron_variant		1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1779+8637C>A		intron_variant				ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 59002 AN: 109464 Hom.: 13307 Cov.: 22 AF XY: 0.547 AC XY: 17405 AN XY: 31802

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.686

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.539 AC: 59003 AN: 109504 Hom.: 13306 Cov.: 22 AF XY: 0.547 AC XY: 17413 AN XY: 31852

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.594

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.566

Gnomad4 FIN AF: 0.731

Gnomad4 NFE AF: 0.692

Gnomad4 OTH AF: 0.560

Alfa AF: 0.637 Hom.: 32045

Bravo AF: 0.519

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.42

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: rs6643622; hg19: chrX-154173530;