rs5945270

chrX-154994928-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.389-1780G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 112,041 control chromosomes in the GnomAD database, including 66 homozygotes. There are 954 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 0.030 (66 hom., 954 hem., cov: 23)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694

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=-0.98).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0295 (3306/112041) while in subpopulation NFE AF= 0.0425 (2259/53142). AF 95% confidence interval is 0.041. There are 66 homozygotes in gnomad4. There are 954 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 66 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.389-1780G>A		intron_variant		ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.389-1780G>A		intron_variant		1	NM_000132.4	P1
F8	ENST00000423959.5	c.284-1780G>A		intron_variant		3
F8	ENST00000453950.1	c.371-1780G>A		intron_variant		3
F8	ENST00000647125.1	c.*175-1780G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 3311 AN: 111988 Hom.: 66 Cov.: 23 AF XY: 0.0280 AC XY: 956 AN XY: 34186

Gnomad AFR AF: 0.00532

Gnomad AMI AF: 0.0774

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0325

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

GnomAD4 genome AF: 0.0295 AC: 3306 AN: 112041 Hom.: 66 Cov.: 23 AF XY: 0.0279 AC XY: 954 AN XY: 34249

Gnomad4 AFR AF: 0.00530

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.00140

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.0425

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0392 Hom.: 287

Bravo AF: 0.0261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.84
Dann	Benign	0.28

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: rs5945270; hg19: chrX-154223203;