rs4905558

Variant names:

• chr14-96879469-G-A
• rs4905558
• NM_003384.3:c.1160-1708G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000216639.8(VRK1):​c.1160-1708G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 151,874 control chromosomes in the GnomAD database, including 29,555 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29555 hom., cov: 31)
• Consequence: VRK1 ENST00000216639.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216639.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	NM_003384.3	MANE Select	c.1160-1708G>A		intron	N/A	NP_003375.1
	VRK1	NM_001411051.1		c.1232-1708G>A		intron	N/A	NP_001397980.1
	VRK1	NM_001411053.1		c.1157-1708G>A		intron	N/A	NP_001397982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.1160-1708G>A		intron	N/A	ENSP00000216639.3
	VRK1	ENST00000679770.1		c.1228-1708G>A		intron	N/A	ENSP00000505214.1
	VRK1	ENST00000679462.1		c.1195-1708G>A		intron	N/A	ENSP00000506011.1

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93448 AN: 151756 Hom.: 29532 Cov.: 31

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.605

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

GnomAD4 genome AF: 0.616 AC: 93511 AN: 151874 Hom.: 29555 Cov.: 31 AF XY: 0.613 AC XY: 45449 AN XY: 74202

African (AFR) AF: 0.663 AC: 27429 AN: 41374

American (AMR) AF: 0.524 AC: 7995 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3468

East Asian (EAS) AF: 0.156 AC: 806 AN: 5170

South Asian (SAS) AF: 0.607 AC: 2919 AN: 4812

European-Finnish (FIN) AF: 0.609 AC: 6410 AN: 10526

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43769 AN: 67956

Other (OTH) AF: 0.600 AC: 1263 AN: 2106

Alfa AF: 0.624 Hom.: 87278

Bravo AF: 0.609

Asia WGS AF: 0.429 AC: 1495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.038
DANN	Benign	0.26
PhyloP100		-0.82
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: rs4905558; hg19: chr14-97345806;