rs4074307

Positions:

• chrX-154901948-A-G

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.6115+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 584,885 control chromosomes in the GnomAD database, including 26,012 homozygotes. There are 65,023 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 (9728 hom., 13202 hem., cov: 22)
  • Exomes 𝑓: 0.30 (16284 hom. 51821 hem.)
• Consequence: F8 NM_000132.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.411

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=-0.88).
• BP6: Variant X-154901948-A-G is Benign according to our data. Variant chrX-154901948-A-G is described in ClinVar as [Benign]. Clinvar id is 1253881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.6115+103T>C		intron_variant		ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6115+103T>C		intron_variant		1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes AF: 0.426 AC: 46928 AN: 110253 Hom.: 9727 Cov.: 22 AF XY: 0.404 AC XY: 13152 AN XY: 32517

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.289

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.304 AC: 144083 AN: 474575 Hom.: 16284 AF XY: 0.308 AC XY: 51821 AN XY: 168477

Gnomad4 AFR exome AF: 0.810

Gnomad4 AMR exome AF: 0.446

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.426 AC: 46977 AN: 110310 Hom.: 9728 Cov.: 22 AF XY: 0.405 AC XY: 13202 AN XY: 32584

Gnomad4 AFR AF: 0.809

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.408

Alfa AF: 0.311 Hom.: 9812

Bravo AF: 0.455

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.85

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: rs4074307; hg19: chrX-154130223;