rs9934438

Positions:

• chr16-31093557-G-A
• chr16-31093557-G-C

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.174-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,543,178 control chromosomes in the GnomAD database, including 119,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9986 hom., cov: 29)
  • Exomes 𝑓: 0.38 (109226 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: drug response reviewed by expert panel P:1 B:2 O:4
• Conservation: PhyloP100: 1.31

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=-0.72).
• BP6: Variant 16-31093557-G-A is Benign according to our data. Variant chr16-31093557-G-A is described in ClinVar as [drug_response]. Clinvar id is 37344.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, drug_response=3}. Variant chr16-31093557-G-A is described in Lovd as [Benign]. Variant chr16-31093557-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.174-136C>T		intron_variant		ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.174-136C>T		intron_variant			NP_001298240.1
VKORC1	NM_206824.3	c.173+1000C>T		intron_variant			NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.174-136C>T		intron_variant		1	NM_024006.6	ENSP00000378426	P1

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48370 AN: 151546 Hom.: 9985 Cov.: 29

Gnomad AFR AF: 0.0999

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.380 AC: 528705 AN: 1391514 Hom.: 109226 Cov.: 33 AF XY: 0.376 AC XY: 257779 AN XY: 685662

Gnomad4 AFR exome AF: 0.0931

Gnomad4 AMR exome AF: 0.451

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.392

GnomAD4 genome AF: 0.319 AC: 48369 AN: 151664 Hom.: 9986 Cov.: 29 AF XY: 0.321 AC XY: 23820 AN XY: 74112

Gnomad4 AFR AF: 0.0996

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.893

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.389

Alfa AF: 0.381 Hom.: 17795

Bravo AF: 0.323

Asia WGS AF: 0.460 AC: 1602 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Benign:2 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

Warfarin response Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
drug response, no assertion criteria provided	research	Pharmacogenomics Lab, Chungbuk National University	Aug 31, 2010	- likely responsive

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 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. -

Vitamin K-Dependent Clotting Factors Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 29, 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

phenprocoumon response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

acenocoumarol response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A 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	-0.72
CADD	Benign	13
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9934438; hg19: chr16-31104878;