rs17708472

chr16-31094032-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024006.6(VKORC1):c.173+525C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 961,844 control chromosomes in the GnomAD database, including 21,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2529 hom., cov: 30)
  • Exomes 𝑓: 0.20 (18737 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.914

Genes affected

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-31094032-G-A is Benign according to our data. Variant chr16-31094032-G-A is described in ClinVar as [Benign]. Clinvar id is 225960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1	NM_024006.6	c.173+525C>T		intron_variant		ENST00000394975.3
VKORC1	NM_001311311.2	c.173+525C>T		intron_variant
VKORC1	NM_206824.3	c.173+525C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3	c.173+525C>T		intron_variant		1	NM_024006.6	P1
	ENST00000624508.1	n.306G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24884 AN: 151630 Hom.: 2529 Cov.: 30

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.204 AC: 165028 AN: 810098 Hom.: 18737 Cov.: 11 AF XY: 0.202 AC XY: 82709 AN XY: 408682

Gnomad4 AFR exome AF: 0.0547

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.00158

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.164 AC: 24885 AN: 151746 Hom.: 2529 Cov.: 30 AF XY: 0.162 AC XY: 12012 AN XY: 74138

Gnomad4 AFR AF: 0.0626

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.163

Alfa AF: 0.213 Hom.: 6372

Bravo AF: 0.152

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.8
Dann	Benign	0.82

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: rs17708472; hg19: chr16-31105353;