dbSNP rs193921078: VKORC1L1:p.Glu165Lys (chr7-65954262-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

2 publications found

Variant links:

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]

VKORC1L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VKORC1L1	NM_173517.6 link	c.493G>A	p.Glu165Lys	missense_variant	Exon 3 of 3	ENST00000360768.5	NP_775788.2
VKORC1L1	NM_001284342.3 link	c.383G>A	p.Arg128Gln	missense_variant	Exon 2 of 2		NP_001271271.1
VKORC1L1	XM_047419923.1 link	c.782G>A	p.Arg261Gln	missense_variant	Exon 4 of 4		XP_047275879.1
VKORC1L1	XM_011515831.3 link	c.406G>A	p.Glu136Lys	missense_variant	Exon 4 of 4		XP_011514133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VKORC1L1	ENST00000360768.5 link	c.493G>A	p.Glu165Lys	missense_variant	Exon 3 of 3	1	NM_173517.6	ENSP00000353998.2
VKORC1L1	ENST00000648187.1 link	c.634G>A	p.Glu212Lys	missense_variant	Exon 3 of 3			ENSP00000497458.1
VKORC1L1	ENST00000434382.2 link	c.383G>A	p.Arg128Gln	missense_variant	Exon 2 of 2	2		ENSP00000403077.2
VKORC1L1	ENST00000648179.1 link	c.493G>A	p.Glu165Lys	missense_variant	Exon 3 of 3			ENSP00000497394.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251396

AF XY:

0.00000736

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0049

.;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

.;L;L

PhyloP100

7.5

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.2

.;.;N

REVEL

Uncertain

0.64

Sift

Benign

0.23

.;.;T

Sift4G

Benign

0.40

.;.;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

GERP RS

5.8

Varity_R

0.21

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over