14-96833516-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003384.3(VRK1):c.45A>G(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,613,514 control chromosomes in the GnomAD database, including 116,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8727 hom., cov: 33)

Exomes 𝑓: 0.38 ( 107522 hom. )

Consequence

VRK1
NM_003384.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.762

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 1A
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp
microcephaly-complex motor and sensory axonal neuropathy syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 14-96833516-A-G is Benign according to our data. Variant chr14-96833516-A-G is described in ClinVar as Benign. ClinVar VariationId is 130731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.762 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK1	NM_003384.3 link	c.45A>G	p.Ala15Ala	synonymous_variant	Exon 2 of 13	ENST00000216639.8	NP_003375.1	Q99986

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK1	ENST00000216639.8 link	c.45A>G	p.Ala15Ala	synonymous_variant	Exon 2 of 13	1	NM_003384.3	ENSP00000216639.3		Q99986

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49639

AN:

152006

Hom.:

8729

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.336

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.429

Gnomad FIN

AF:

0.400

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.326

GnomAD2 exomes

AF:

0.356

AC:

89305

AN:

251022

AF XY:

0.366

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.397

Gnomad NFE exome

AF:

0.390

Gnomad OTH exome

AF:

0.371

GnomAD4 exome

AF:

0.378

AC:

553130

AN:

1461390

Hom.:

107522

Cov.:

AF XY:

0.381

AC XY:

276643

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.207

AC:

6920

AN:

33448

American (AMR)

AF:

0.354

AC:

15834

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

8081

AN:

26114

East Asian (EAS)

AF:

0.105

AC:

4175

AN:

39674

South Asian (SAS)

AF:

0.428

AC:

36918

AN:

86250

European-Finnish (FIN)

AF:

0.391

AC:

20861

AN:

53374

Middle Eastern (MID)

AF:

0.328

AC:

1889

AN:

5766

European-Non Finnish (NFE)

AF:

0.393

AC:

436686

AN:

1111696

Other (OTH)

AF:

0.361

AC:

21766

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

19421

38841

58262

77682

97103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13482

26964

40446

53928

67410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.326

AC:

49657

AN:

152124

Hom.:

8727

Cov.:

AF XY:

0.331

AC XY:

24636

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.216

AC:

8988

AN:

41530

American (AMR)

AF:

0.336

AC:

5129

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1107

AN:

3470

East Asian (EAS)

AF:

0.111

AC:

573

AN:

5174

South Asian (SAS)

AF:

0.430

AC:

2076

AN:

4824

European-Finnish (FIN)

AF:

0.400

AC:

4229

AN:

10564

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.390

AC:

26510

AN:

67968

Other (OTH)

AF:

0.321

AC:

678

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1666

3332

4998

6664

8330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.368

Hom.:

15220

Bravo

AF:

0.315

Asia WGS

AF:

0.256

AC:

889

AN:

3478

EpiCase

AF:

0.386

EpiControl

AF:

0.383

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 1A

Benign:4

Nov 19, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Isolated microphthalmia 2

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.7

(source)

DANN

Benign

0.46

PhyloP100

-0.76

PromoterAI

0.041

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over