rs17878259

Positions:

• chr16-31095322-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BS1 BS2

The XM_047435012.1(LOC124903680):​c.57T>C​(p.Ser19=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,469,334 control chromosomes in the GnomAD database, including 20 homozygotes. 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 0.0069 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: LOC124903680 XM_047435012.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960

Genes affected

LOC124903680 (HGNC:):

VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-0.096 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0069 (1033/149710) while in subpopulation AFR AF= 0.0242 (979/40510). AF 95% confidence interval is 0.0229. There are 7 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC124903680	XM_047435012.1	c.57T>C	p.Ser19=	synonymous_variant	1/1		XP_047290968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000624508.1	n.1596A>G		non_coding_transcript_exon_variant	1/1
VKORC1	ENST00000420057.2	c.245+67T>C		intron_variant		2		ENSP00000437064
VKORC1	ENST00000498155.1	c.270+67T>C		intron_variant		5		ENSP00000417662

Frequencies

GnomAD3 genomes AF: 0.00690 AC: 1032 AN: 149614 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000662 AC: 873 AN: 1319624 Hom.: 13 Cov.: 29 AF XY: 0.000541 AC XY: 348 AN XY: 642732

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000306

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000575

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00690 AC: 1033 AN: 149710 Hom.: 7 Cov.: 32 AF XY: 0.00674 AC XY: 492 AN XY: 72968

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.00339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00492 Hom.: 1

Bravo AF: 0.00844

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.78

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17878259; hg19: chr16-31106643;