rs139476915

Positions:

chr14-96856555-G-T

Variant summary

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

The NM_003384.3(VRK1):c.858G>T(p.Met286Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000966 in 1,613,638 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

VRK1
NM_003384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:12B:2

Conservation

PhyloP100: 5.12

Variant links:

Genes affected

VRK1 (HGNC:12718): (VRK serine/threonine kinase 1) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human tissues and has increased expression in actively dividing cells, such as those in testis, thymus, fetal liver, and carcinomas. Its protein localizes to the nucleus and has been shown to promote the stability and nuclear accumulation of a transcriptionally active p53 molecule and, in vitro, to phosphorylate Thr18 of p53 and reduce p53 ubiquitination. This gene, therefore, may regulate cell proliferation. This protein also phosphorylates histone, casein, and the transcription factors ATF2 (activating transcription factor 2) and c-JUN. [provided by RefSeq, Jul 2008]

VRK1 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=0.02928868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VRK1	NM_003384.3 link	c.858G>T	p.Met286Ile	missense_variant	10/13	ENST00000216639.8	NP_003375.1	Q99986

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VRK1	ENST00000216639.8 link	c.858G>T	p.Met286Ile	missense_variant	10/13	1	NM_003384.3	ENSP00000216639.3		Q99986

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000797

AC:

200

AN:

250858

Hom.:

AF XY:

0.000885

AC XY:

120

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00101

AC:

1475

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

756

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00175

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.000545

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000955

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000667

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 25, 2024	BP4, PM1, PM2_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2013	- -

Pontocerebellar hypoplasia type 1A

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 286 of the VRK1 protein (p.Met286Ile). This variant is present in population databases (rs139476915, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 130730). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 13, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Distal spinal muscular atrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Oct 01, 2020

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 13, 2023

Variant summary: VRK1 c.858G>T (p.Met286Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 250858 control chromosomes, predominantly at a frequency of 0.0016 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in VRK1 causing Pontocerebellar Hypoplasia, Type 1A phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.858G>T has been reported in the literature in the compound heterozygous state in two siblings affected with distal spinal muscle atrophy (Demaegd_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; six submitters classified the variant as uncertain significance, one classified it as likely pathogenic, and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Congenital pontocerebellar hypoplasia type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 18, 2020

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The p.M286I variant (also known as c.858G>T), located in coding exon 9 of the VRK1 gene, results from a G to T substitution at nucleotide position 858. The methionine at codon 286 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

VRK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

0.023

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.012

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.39

REVEL

Benign

0.18

Sift

Benign

0.22

Sift4G

Benign

0.36

Polyphen

0.88

Vest4

0.49

MutPred

0.55

Gain of catalytic residue at N281 (P = 0.0027);

MVP

0.49

MPC

0.35

ClinPred

0.047

GERP RS

4.7

Varity_R

0.29

gMVP

0.65

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