rs6655259

Positions:

• chrX-155000669-C-T

Variant summary

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

The NM_000132.4(F8):​c.144-1069G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 111,716 control chromosomes in the GnomAD database, including 37 homozygotes. There are 1,011 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 0.031 (37 hom., 1011 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217

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=-0.91).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0306 (3419/111716) while in subpopulation AFR AF= 0.0392 (1205/30757). AF 95% confidence interval is 0.0373. There are 37 homozygotes in gnomad4. There are 1011 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.144-1069G>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.144-1069G>A		intron_variant		1	NM_000132.4	ENSP00000353393.4
F8	ENST00000423959.5	c.39-1069G>A		intron_variant		3		ENSP00000409446.1
F8	ENST00000453950.1	c.126-1069G>A		intron_variant		3		ENSP00000389153.1
F8	ENST00000647125.1	n.122-1069G>A		intron_variant				ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 3421 AN: 111665 Hom.: 37 Cov.: 23 AF XY: 0.0298 AC XY: 1009 AN XY: 33891

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0190

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0697

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00669

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0416

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

GnomAD4 genome AF: 0.0306 AC: 3419 AN: 111716 Hom.: 37 Cov.: 23 AF XY: 0.0298 AC XY: 1011 AN XY: 33952

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.0697

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00671

Gnomad4 FIN AF: 0.0462

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0410

Alfa AF: 0.0364 Hom.: 193

Bravo AF: 0.0293

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.49
DANN	Benign	0.71

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: rs6655259; hg19: chrX-154228944;