rs61742245

chr16-31094624-C-Achr16-31094624-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM5 BP4_Strong BP6_Strong BS2

The NM_024006.6(VKORC1):c.106G>T(p.Asp36Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,606,390 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D36G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (23 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: drug response reviewed by expert panel P:1 U:1 B:5 O:1
• Conservation: PhyloP100: 0.946

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 -8 ACMG points.

• PM1: In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 26 pathogenic changes around while only 3 benign (90%) in NM_024006.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.035001844).
• BP6: Variant 16-31094624-C-A is Benign according to our data. Variant chr16-31094624-C-A is described in ClinVar as [drug_response]. Clinvar id is 2212.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, drug_response=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1	NM_024006.6	c.106G>T	p.Asp36Tyr	missense_variant	1/3	ENST00000394975.3
VKORC1	NM_001311311.2	c.106G>T	p.Asp36Tyr	missense_variant	1/4
VKORC1	NM_206824.3	c.106G>T	p.Asp36Tyr	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3	c.106G>T	p.Asp36Tyr	missense_variant	1/3	1	NM_024006.6	P1
	ENST00000624508.1	n.898C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152260 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00240 AC: 547 AN: 227482 Hom.: 4 AF XY: 0.00235 AC XY: 295 AN XY: 125414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000913

Gnomad FIN exome AF: 0.0000558

Gnomad NFE exome AF: 0.000694

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00134 AC: 1947 AN: 1454012 Hom.: 23 Cov.: 32 AF XY: 0.00143 AC XY: 1032 AN XY: 723218

Gnomad4 AFR exome AF: 0.00234

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.0387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000642

Gnomad4 FIN exome AF: 0.0000401

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152378 Hom.: 4 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74516

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00450 Hom.: 2

Bravo AF: 0.00176

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.00170 AC: 205

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	VKORC1: PM5, PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2023	- -

Warfarin response Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Thrombus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

VKORC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Nov 18, 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
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.056
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.035	T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.00015	A;A;A;A;A
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0, 0.99	.;.;.;D;.;D
Vest4		0.55, 0.45, 0.41, 0.42
MVP		0.84
MPC		1.3
ClinPred		0.12	T
GERP RS		-0.065
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61742245; hg19: chr16-31105945;