Variant chr19-50007706-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016440.4(VRK3):c.410C>T(p.Pro137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

VRK3
NM_016440.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

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 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=0.2595622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VRK3	NM_016440.4 linkuse as main transcript	c.410C>T	p.Pro137Leu	missense_variant	5/15	ENST00000316763.8	NP_057524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VRK3	ENST00000316763.8 linkuse as main transcript	c.410C>T	p.Pro137Leu	missense_variant	5/15	1	NM_016440.4	ENSP00000324636	P2	Q8IV63-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 16, 2024

The c.410C>T (p.P137L) alteration is located in exon 5 (coding exon 3) of the VRK3 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the proline (P) at amino acid position 137 to be replaced by a leucine (L). 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

0.096

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;.;.;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.26

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

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.8

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

D;D;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0020

D;D;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.040

D;D;D;D;D;D;D;D;.;.;.;D

Polyphen

1.0

D;.;D;.;D;.;D;.;.;.;.;.

Vest4

0.29

MutPred

0.25

Loss of glycosylation at P137 (P = 0.0618);.;Loss of glycosylation at P137 (P = 0.0618);.;Loss of glycosylation at P137 (P = 0.0618);.;Loss of glycosylation at P137 (P = 0.0618);Loss of glycosylation at P137 (P = 0.0618);.;Loss of glycosylation at P137 (P = 0.0618);.;Loss of glycosylation at P137 (P = 0.0618);

MVP

0.86

MPC

0.61

ClinPred

0.98

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over