rs73563631

Positions:

• chrX-154880587-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000132.4(F8):​c.6429+15490T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 112,399 control chromosomes in the GnomAD database, including 24 homozygotes. There are 385 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 0.012 (24 hom., 385 hem., cov: 22)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652

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=-1.03).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1386/112399) while in subpopulation AFR AF= 0.0425 (1313/30925). AF 95% confidence interval is 0.0405. There are 24 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6429+15490T>C		intron_variant		ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.24+5547T>C		intron_variant			NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6429+15490T>C		intron_variant		1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.24+5547T>C		intron_variant		1		ENSP00000327895.6
F8	ENST00000644698.1	c.162+1450T>C		intron_variant				ENSP00000495706.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1388 AN: 112344 Hom.: 24 Cov.: 22 AF XY: 0.0112 AC XY: 386 AN XY: 34504

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.0145

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

GnomAD4 genome AF: 0.0123 AC: 1386 AN: 112399 Hom.: 24 Cov.: 22 AF XY: 0.0111 AC XY: 385 AN XY: 34569

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.0117 Hom.: 35

Bravo AF: 0.0145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.47

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: rs73563631; hg19: chrX-154108862;