19-49988411-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016440.4(VRK3):c.1178G>A(p.Cys393Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

VRK3
NM_016440.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.175

Variant links:

Genes affected

VRK3 (HGNC:18996): (VRK serine/threonine kinase 3) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. In both human and mouse, this gene has substitutions at several residues within the ATP binding motifs that in other kinases have been shown to be required for catalysis. In vitro assays indicate the protein lacks phosphorylation activity. The protein, however, likely retains its substrate binding capability. This gene is widely expressed in human tissues and its protein localizes to the nucleus. Alternative splicing results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]

VRK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051217616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VRK3	NM_016440.4 linkuse as main transcript	c.1178G>A	p.Cys393Tyr	missense_variant	12/15	ENST00000316763.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VRK3	ENST00000316763.8 linkuse as main transcript	c.1178G>A	p.Cys393Tyr	missense_variant	12/15	1	NM_016440.4	P2	Q8IV63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251422

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135876

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:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726922

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:

0.000417

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

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:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000306

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

Nov 02, 2023

The c.1178G>A (p.C393Y) alteration is located in exon 12 (coding exon 10) of the VRK3 gene. This alteration results from a G to A substitution at nucleotide position 1178, causing the cysteine (C) at amino acid position 393 to be replaced by a tyrosine (Y). 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

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.019

T;.;T;.;T;.;.;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.037

M_CAP

Benign

0.0067

MetaRNN

Benign

0.051

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;.;L;.;L;.;L;.;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

N;N;.;.;.;.;.;.;.

REVEL

Benign

0.084

Sift

Benign

1.0

T;T;.;.;.;.;.;.;.

Sift4G

Benign

0.21

T;T;T;T;T;T;T;T;T

Polyphen

0.92

P;.;P;.;P;.;P;.;.

Vest4

0.37

MutPred

0.39

Loss of catalytic residue at L394 (P = 0.0274);.;Loss of catalytic residue at L394 (P = 0.0274);.;Loss of catalytic residue at L394 (P = 0.0274);.;Loss of catalytic residue at L394 (P = 0.0274);.;Loss of catalytic residue at L394 (P = 0.0274);

MVP

0.49

MPC

0.74

ClinPred

0.098

GERP RS

0.38

Varity_R

0.20

gMVP

0.48

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