14-96833254-G-A

Variant names:

• chr14-96833254-G-A
• rs10134437
• NM_003384.3:c.-5-213G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003384.3(VRK1):​c.-5-213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,114 control chromosomes in the GnomAD database, including 1,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1636 hom., cov: 32)
• Consequence: VRK1 NM_003384.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.556
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-96833254-G-A is Benign according to our data. Variant chr14-96833254-G-A is described in ClinVar as [Benign]. Clinvar id is 675686.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK1	NM_003384.3	c.-5-213G>A		intron_variant	Intron 1 of 12	ENST00000216639.8	NP_003375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK1	ENST00000216639.8	c.-5-213G>A		intron_variant	Intron 1 of 12	1	NM_003384.3	ENSP00000216639.3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19793 AN: 151996 Hom.: 1636 Cov.: 32

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.130 AC: 19797 AN: 152114 Hom.: 1636 Cov.: 32 AF XY: 0.128 AC XY: 9553 AN XY: 74356

African (AFR) AF: 0.0512 AC: 2125 AN: 41504

American (AMR) AF: 0.105 AC: 1603 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3470

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5188

South Asian (SAS) AF: 0.0556 AC: 268 AN: 4820

European-Finnish (FIN) AF: 0.169 AC: 1782 AN: 10572

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12911 AN: 67970

Other (OTH) AF: 0.139 AC: 293 AN: 2112

Alfa AF: 0.154 Hom.: 230

Bravo AF: 0.123

Asia WGS AF: 0.0630 AC: 217 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.68
PhyloP100		-0.56
PromoterAI		-0.0030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10134437; hg19: chr14-97299591;