7-65954220-C-T

Position:

chr7-65954220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173517.6(VKORC1L1):c.451C>T(p.Leu151Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

VKORC1L1
NM_173517.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14224356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1L1	NM_173517.6 linkuse as main transcript	c.451C>T	p.Leu151Phe	missense_variant	3/3	ENST00000360768.5	NP_775788.2
VKORC1L1	NM_001284342.3 linkuse as main transcript	c.341C>T	p.Pro114Leu	missense_variant	2/2		NP_001271271.1
VKORC1L1	XM_047419923.1 linkuse as main transcript	c.740C>T	p.Pro247Leu	missense_variant	4/4		XP_047275879.1
VKORC1L1	XM_011515831.3 linkuse as main transcript	c.364C>T	p.Leu122Phe	missense_variant	4/4		XP_011514133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1L1	ENST00000360768.5 linkuse as main transcript	c.451C>T	p.Leu151Phe	missense_variant	3/3	1	NM_173517.6	ENSP00000353998	P1	Q8N0U8-1
VKORC1L1	ENST00000648187.1 linkuse as main transcript	c.592C>T	p.Leu198Phe	missense_variant	3/3			ENSP00000497458
VKORC1L1	ENST00000434382.2 linkuse as main transcript	c.341C>T	p.Pro114Leu	missense_variant	2/2	2		ENSP00000403077		Q8N0U8-2
VKORC1L1	ENST00000648179.1 linkuse as main transcript	c.451C>T	p.Leu151Phe	missense_variant	3/3			ENSP00000497394	P1	Q8N0U8-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251452

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Jun 18, 2021

The c.451C>T (p.L151F) alteration is located in exon 3 (coding exon 3) of the VKORC1L1 gene. This alteration results from a C to T substitution at nucleotide position 451, causing the leucine (L) at amino acid position 151 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

0.11

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Benign

7.8

DANN

Benign

0.95

DEOGEN2

Benign

0.39

.;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.65

T;T;.

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Uncertain

0.099

MutationAssessor

Benign

0.69

.;N;N

MutationTaster

Benign

0.89

D;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

.;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.67

.;.;T

Sift4G

Benign

0.51

.;.;T

Polyphen

0.0020

.;B;B

Vest4

0.20

MVP

0.16

MPC

0.94

ClinPred

0.033

GERP RS

0.33

Varity_R

0.052

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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