16-31092864-T-C

Position:

• chr16-31092864-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The ENST00000319788.11(VKORC1):​c.284A>G​(p.Asp95Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 948,172 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/16 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: VKORC1 ENST00000319788.11 missense, splice_region
• Scores: Splicing: ADA: 0.0002272
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.299

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 -11 ACMG points.

• PM1: In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 25 pathogenic changes around while only 4 benign (86%) in ENST00000319788.11
• BP4: Computational evidence support a benign effect (MetaRNN=0.0044502616).
• BP6: Variant 16-31092864-T-C is Benign according to our data. Variant chr16-31092864-T-C is described in ClinVar as [Benign]. Clinvar id is 3033207.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00133 (1062/798628) while in subpopulation SAS AF= 0.0161 (998/61806). AF 95% confidence interval is 0.0153. There are 17 homozygotes in gnomad4_exome. There are 769 alleles in male gnomad4_exome subpopulation. Median coverage is 10. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.283+448A>G		intron_variant		ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.286A>G	p.Met96Val	missense_variant, splice_region_variant	3/4		NP_001298240.1
VKORC1	NM_206824.3	c.174-1522A>G		intron_variant			NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.283+448A>G		intron_variant		1	NM_024006.6	ENSP00000378426	P1

Frequencies

GnomAD3 genomes AF: 0.000576 AC: 86 AN: 149426 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0173

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000995

GnomAD3 exomes AF: 0.00314 AC: 227 AN: 72394 Hom.: 3 AF XY: 0.00376 AC XY: 152 AN XY: 40384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000720

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00133 AC: 1062 AN: 798628 Hom.: 17 Cov.: 10 AF XY: 0.00194 AC XY: 769 AN XY: 396306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000312

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.000575 AC: 86 AN: 149544 Hom.: 3 Cov.: 31 AF XY: 0.000781 AC XY: 57 AN XY: 72940

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000984

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.00764 AC: 108

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

VKORC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	4.1
DANN	Benign	0.73
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	2.9	N
REVEL	Benign	0.23
Sift	Benign	0.41	T
Sift4G	Benign	0.73	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.47		Loss of stability (P = 0.0332);
MVP		0.75
ClinPred		0.023	T
GERP RS		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.044
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: rs371197517; hg19: chr16-31104185;