NM_003384.3:c.26C>T

Variant names:

• chr14-96833497-C-T
• rs771269721
• NM_003384.3:c.26C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003384.3(VRK1):​c.26C>T​(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: VRK1 NM_003384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.53
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15369454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK1	NM_003384.3	c.26C>T	p.Ala9Val	missense_variant	Exon 2 of 13	ENST00000216639.8	NP_003375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK1	ENST00000216639.8	c.26C>T	p.Ala9Val	missense_variant	Exon 2 of 13	1	NM_003384.3	ENSP00000216639.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251000 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461384 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727004

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.0000447 AC: 2 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111714

Other (OTH) AF: 0.0000331 AC: 2 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pontocerebellar hypoplasia type 1A Uncertain:2

Jul 20, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with valine at codon 9 of the VRK1 protein (p.Ala9Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs771269721, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with VRK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.057
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		0.57	P
Vest4		0.35
MutPred		0.28		Gain of catalytic residue at R11 (P = 0.0668);
MVP		0.39
MPC		0.28
ClinPred		0.28	T
GERP RS		5.0
PromoterAI		-0.011	Neutral
Varity_R		0.085
gMVP		0.56
Mutation Taster		=87/13	polymorphism

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: rs771269721; hg19: chr14-97299834;