19-49989726-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016440.4(VRK3):c.1009G>A(p.Gly337Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VRK3 NM_016440.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

VRK3 (HGNC:18996): (VRK serine/threonine kinase 3) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. In both human and mouse, this gene has substitutions at several residues within the ATP binding motifs that in other kinases have been shown to be required for catalysis. In vitro assays indicate the protein lacks phosphorylation activity. The protein, however, likely retains its substrate binding capability. This gene is widely expressed in human tissues and its protein localizes to the nucleus. Alternative splicing results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VRK3	NM_016440.4	c.1009G>A	p.Gly337Ser	missense_variant	11/15	ENST00000316763.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VRK3	ENST00000316763.8	c.1009G>A	p.Gly337Ser	missense_variant	11/15	1	NM_016440.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.1009G>A (p.G337S) alteration is located in exon 11 (coding exon 9) of the VRK3 gene. This alteration results from a G to A substitution at nucleotide position 1009, causing the glycine (G) at amino acid position 337 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.;T;.;T;.;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;M;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	D;D;.;.;.;.;.;.;.
REVEL	Benign	0.21
Sift	Uncertain	0.020	D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;.;D;.;.
Vest4		0.56
MutPred		0.60		Gain of disorder (P = 0.0941);.;Gain of disorder (P = 0.0941);.;Gain of disorder (P = 0.0941);.;Gain of disorder (P = 0.0941);.;Gain of disorder (P = 0.0941);
MVP		0.61
MPC		0.60
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.58
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50492983;