rs193921078

chr7-65954262-G-Achr7-65954262-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173517.6(VKORC1L1):c.493G>A(p.Glu165Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: VKORC1L1 NM_173517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49

Genes affected

VKORC1L1 (HGNC:21492): (vitamin K epoxide reductase complex subunit 1 like 1) This gene encodes an enzyme important in the vitamin K cycle, which is involved in the carboxylation of glutamate residues present in vitamin K-dependent proteins. The encoded enzyme catalyzes the de-epoxidation of vitamin K 2,3-epoxide. Oxidative stress may upregulate expression of this gene and the encoded protein may protect cells and membrane proteins form oxidative damage. This gene and a related gene (Gene ID: 79001) may have arisen by gene duplication of an ancestral gene. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VKORC1L1	NM_173517.6	c.493G>A	p.Glu165Lys	missense_variant	3/3	ENST00000360768.5
VKORC1L1	NM_001284342.3	c.383G>A	p.Arg128Gln	missense_variant	2/2
VKORC1L1	XM_047419923.1	c.782G>A	p.Arg261Gln	missense_variant	4/4
VKORC1L1	XM_011515831.3	c.406G>A	p.Glu136Lys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1L1	ENST00000360768.5	c.493G>A	p.Glu165Lys	missense_variant	3/3	1	NM_173517.6	P1
VKORC1L1	ENST00000648187.1	c.634G>A	p.Glu212Lys	missense_variant	3/3
VKORC1L1	ENST00000434382.2	c.383G>A	p.Arg128Gln	missense_variant	2/2	2
VKORC1L1	ENST00000648179.1	c.493G>A	p.Glu165Lys	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
Polyphen		1.0	.;D;D
Vest4		0.47
MutPred		0.40		.;Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);
MVP		0.50
MPC		1.3
ClinPred		0.65	D
GERP RS		5.8
Varity_R		0.21

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: rs193921078; hg19: chr7-65419249; COSMIC: COSV62489066;