Variant 7-65873516-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_173517.6(VKORC1L1):c.145C>T(p.Leu49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,590,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

VKORC1L1
NM_173517.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0200

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
VKORC1L1	NM_173517.6 linkuse as main transcript	c.145C>T	p.Leu49Phe	missense_variant	1/3	ENST00000360768.5
VKORC1L1	NM_001284342.3 linkuse as main transcript	c.145C>T	p.Leu49Phe	missense_variant	1/2
VKORC1L1	XM_047419923.1 linkuse as main transcript	c.286C>T	p.Leu96Phe	missense_variant	1/4
VKORC1L1	XM_011515831.3 linkuse as main transcript	c.107+1778C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VKORC1L1	ENST00000360768.5 linkuse as main transcript	c.145C>T	p.Leu49Phe	missense_variant	1/3	1	NM_173517.6	P1	Q8N0U8-1
VKORC1L1	ENST00000648187.1 linkuse as main transcript	c.286C>T	p.Leu96Phe	missense_variant	1/3
VKORC1L1	ENST00000434382.2 linkuse as main transcript	c.145C>T	p.Leu49Phe	missense_variant	1/2	2			Q8N0U8-2
VKORC1L1	ENST00000648179.1 linkuse as main transcript	c.145C>T	p.Leu49Phe	missense_variant	1/3			P1	Q8N0U8-1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

222554

Hom.:

AF XY:

0.0000164

AC XY:

AN XY:

121842

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000298

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1439456

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

716042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

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:

0.0000136

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73748

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.145C>T (p.L49F) alteration is located in exon 1 (coding exon 1) of the VKORC1L1 gene. This alteration results from a C to T substitution at nucleotide position 145, causing the leucine (L) at amino acid position 49 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.00061

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.61

T;T;.;T

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Uncertain

0.093

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.90

Polyphen

0.028

.;B;B;.

Vest4

0.10, 0.20

MutPred

0.56

.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.15

MPC

1.2

ClinPred

0.053

GERP RS

1.3

Varity_R

0.074

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over