16-31093393-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_024006.6(VKORC1):c.202C>T(p.His68Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H68R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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 Likely_benign. Variant got -6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.06757164).
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1	NM_024006.6	c.202C>T	p.His68Tyr	missense_variant	2/3	ENST00000394975.3
VKORC1	NM_001311311.2	c.202C>T	p.His68Tyr	missense_variant	2/4
VKORC1	NM_206824.3	c.173+1164C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1	ENST00000394975.3	c.202C>T	p.His68Tyr	missense_variant	2/3	1	NM_024006.6	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152160 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000358 AC: 90 AN: 251178 Hom.: 2 AF XY: 0.000317 AC XY: 43 AN XY: 135796

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000283 AC: 414 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.000276 AC XY: 201 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.000313

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152276 Hom.: 0 Cov.: 30 AF XY: 0.000282 AC XY: 21 AN XY: 74460

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000316 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	15
Dann	Benign	0.79
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Uncertain	0.086	D
MutationTaster	Benign	0.75	D;N;N;N;N;N
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.43	T;D;D
Sift4G	Uncertain	0.034	D;D;D
Vest4		0.41
MVP		0.86
ClinPred		0.076	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs145273772; hg19: chr16-31104714;