X-154836305-T-C

Position:

• chrX-154836305-T-C

Variant summary

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

The NM_000132.4(F8):​c.*1292A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.99 (38426 hom., 32204 hem., cov: 22)
  • Exomes 𝑓: 1.0 (1 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: F8 NM_000132.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.*1292A>G		3_prime_UTR_variant	26/26	ENST00000360256.9
F8	NM_019863.3	c.*1292A>G		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.*1292A>G		3_prime_UTR_variant	26/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.*1292A>G		3_prime_UTR_variant	5/5	1
F8	ENST00000644698.1	c.*1292A>G		3_prime_UTR_variant	6/6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 109478 AN: 110136 Hom.: 38430 Cov.: 22 AF XY: 0.995 AC XY: 32141 AN XY: 32314 FAILED QC

Gnomad AFR AF: 0.980

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 1.00 AC: 3 AN: 3 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 1 AN XY: 1

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.994 AC: 109532 AN: 110191 Hom.: 38426 Cov.: 22 AF XY: 0.995 AC XY: 32204 AN XY: 32379

Gnomad4 AFR AF: 0.980

Gnomad4 AMR AF: 0.995

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.994

Alfa AF: 0.997 Hom.: 9222

Bravo AF: 0.993

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.65
DANN	Benign	0.81

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: rs1396947; hg19: chrX-154064580;