NM_024006.6:c.352G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. 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. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118L) has been classified as Likely benign.

• 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
• Publications: 5 publications found

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]

VKORC1 Gene-Disease associations (from GenCC):

• vitamin K-dependent clotting factors, combined deficiency of, type 2

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14090008).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	NM_024006.6	MANE Select	c.352G>A	p.Val118Ile	missense	Exon 3 of 3	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.436G>A	p.Val146Ile	missense	Exon 4 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.242G>A	p.Cys81Tyr	missense	Exon 2 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.352G>A	p.Val118Ile	missense	Exon 3 of 3	ENSP00000378426.2	Q9BQB6-1
	VKORC1	ENST00000319788.11	TSL:1	c.434G>A	p.Cys145Tyr	missense	Exon 4 of 4	ENSP00000326135.7	Q9BQB6-2
	VKORC1	ENST00000354895.4	TSL:1	c.242G>A	p.Cys81Tyr	missense	Exon 2 of 2	ENSP00000346969.4	Q9BQB6-3

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.22	T
PhyloP100		0.099
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	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
Varity_R		0.060
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs753570105; hg19: chr16-31102595;