rs7294

chr16-31091000-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The NM_024006.6(VKORC1):c.*134G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,426,034 control chromosomes in the GnomAD database, including 115,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12893 hom., cov: 31)
  • Exomes 𝑓: 0.39 (102978 hom.)
• Consequence: VKORC1 NM_024006.6 3_prime_UTR
• Clinical Significance: drug response reviewed by expert panel B:1 O:1
• Conservation: PhyloP100: 0.00200

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-31091000-C-T is Benign according to our data. Variant chr16-31091000-C-T is described in ClinVar as [drug_response]. Clinvar id is 226016.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1	NM_024006.6	c.*134G>A		3_prime_UTR_variant	3/3	ENST00000394975.3
VKORC1	NM_001311311.2	c.*134G>A		3_prime_UTR_variant	4/4
VKORC1	NM_206824.3	c.*237G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3	c.*134G>A		3_prime_UTR_variant	3/3	1	NM_024006.6	P1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61172 AN: 151832 Hom.: 12858 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.390 AC: 496903 AN: 1274084 Hom.: 102978 Cov.: 19 AF XY: 0.397 AC XY: 250851 AN XY: 631166

Gnomad4 AFR exome AF: 0.464

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.0949

Gnomad4 SAS exome AF: 0.686

Gnomad4 FIN exome AF: 0.388

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.403 AC: 61257 AN: 151950 Hom.: 12893 Cov.: 31 AF XY: 0.407 AC XY: 30239 AN XY: 74270

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.400

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.365

Alfa AF: 0.379 Hom.: 19249

Bravo AF: 0.395

Asia WGS AF: 0.458 AC: 1591 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1B: Level 1B clinical annotations describe variant-drug combinations with a high level of evidence supporting the association but no variant-specific prescribing guidance in an annotated clinical guideline or FDA drug label. Level 1B clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.1
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7294; hg19: chr16-31102321;