Variant 16-31094624-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The ENST00000394975.3(VKORC1):c.106G>A(p.Asp36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D36Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VKORC1
ENST00000394975.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.946

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in ENST00000394975.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VKORC1	NM_024006.6 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	1/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	1/4		NP_001298240.1
VKORC1	NM_206824.3 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	1/2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	1/3	1	NM_024006.6	ENSP00000378426	P1	Q9BQB6-1
	ENST00000624508.1 linkuse as main transcript	n.898C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723218

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

.;.;.;.;.;D

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.80

T;T;T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.58

D;D;D;D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.1

.;.;.;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.0

.;N;D;N;D;N

REVEL

Uncertain

0.33

Sift

Benign

0.21

.;T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.86, 0.0060

.;.;.;P;.;B

Vest4

0.43, 0.20, 0.22, 0.19

MutPred

0.80

Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);Gain of MoRF binding (P = 0.0249);

MVP

0.42

MPC

0.39

ClinPred

0.61

GERP RS

-0.065

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.74

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over