rs4898352

Positions:

• chrX-154903815-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000132.4(F8):​c.5998+91T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 775,751 control chromosomes in the GnomAD database, including 33,605 homozygotes. There are 71,495 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (9839 hom., 13681 hem., cov: 23)
  • Exomes 𝑓: 0.30 (23766 hom. 57814 hem.)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.384

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-154903815-A-T is Benign according to our data. Variant chrX-154903815-A-T is described in ClinVar as [Benign]. Clinvar id is 1251259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.5998+91T>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.5998+91T>A		intron_variant		1	NM_000132.4	ENSP00000353393	P1

Frequencies

GnomAD3 genomes AF: 0.428 AC: 47554 AN: 111046 Hom.: 9838 Cov.: 23 AF XY: 0.410 AC XY: 13635 AN XY: 33240

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.412

GnomAD4 exome AF: 0.299 AC: 198409 AN: 664652 Hom.: 23766 AF XY: 0.308 AC XY: 57814 AN XY: 187544

Gnomad4 AFR exome AF: 0.823

Gnomad4 AMR exome AF: 0.441

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.323

GnomAD4 genome AF: 0.428 AC: 47598 AN: 111099 Hom.: 9839 Cov.: 23 AF XY: 0.411 AC XY: 13681 AN XY: 33303

Gnomad4 AFR AF: 0.816

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.407

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.406

Alfa AF: 0.364 Hom.: 2849

Bravo AF: 0.456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.68
DANN	Benign	0.76

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: rs4898352; hg19: chrX-154132090;