chr16-31091274-C-T

Variant names:

• chr16-31091274-C-T
• rs753570105
• NM_024006.6:c.352G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_024006.6(VKORC1):​c.352G>A​(p.Val118Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990

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]

ENSG00000255439 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_024006.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14090008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.352G>A	p.Val118Ile	missense_variant	Exon 3 of 3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.436G>A	p.Val146Ile	missense_variant	Exon 4 of 4		NP_001298240.1
VKORC1	NM_206824.3	c.242G>A	p.Cys81Tyr	missense_variant	Exon 2 of 2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.352G>A	p.Val118Ile	missense_variant	Exon 3 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.283+2038G>A		intron_variant	Intron 2 of 4	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.18
CADD	Benign	11
DANN	Benign	0.94
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.57	T;T;T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
PROVEAN	Benign	-1.4	N;D;N;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.032	.;B;.;.;.
Vest4		0.13
MutPred		0.30		.;Loss of catalytic residue at L146 (P = 0.0535);.;.;.;
MVP		0.68
ClinPred		0.33	T
GERP RS		-3.2
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: rs753570105; hg19: chr16-31102595;