rs139476915

Variant names:

• chr14-96856555-G-T
• rs139476915
• NM_003384.3:c.858G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_003384.3(VRK1):​c.858G>T​(p.Met286Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000966 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: VRK1 NM_003384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12 B:2 O:1
• Conservation: PhyloP100: 5.12
• Publications: 4 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), Genomics England PanelApp, Ambry Genetics, G2P
• 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a domain Protein kinase (size 280) in uniprot entity VRK1_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_003384.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.02928868).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	NM_003384.3	MANE Select	c.858G>T	p.Met286Ile	missense	Exon 10 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.858G>T	p.Met286Ile	missense	Exon 10 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.858G>T	p.Met286Ile	missense	Exon 10 of 13	NP_001397982.1	A0A7P0T838

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.858G>T	p.Met286Ile	missense	Exon 10 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.858G>T	p.Met286Ile	missense	Exon 10 of 14	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000679462.1		c.858G>T	p.Met286Ile	missense	Exon 9 of 12	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000797 AC: 200 AN: 250858 AF XY: 0.000885

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00101 AC: 1475 AN: 1461406 Hom.: 0 Cov.: 30 AF XY: 0.00104 AC XY: 756 AN XY: 727020

African (AFR) AF: 0.000179 AC: 6 AN: 33472

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00175 AC: 151 AN: 86230

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00113 AC: 1254 AN: 1111662

Other (OTH) AF: 0.000812 AC: 49 AN: 60382

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74428

African (AFR) AF: 0.000120 AC: 5 AN: 41528

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00106 Hom.: 7

Bravo AF: 0.000559

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	not provided (7)
-	3	-	Pontocerebellar hypoplasia type 1A (3)
-	1	-	Congenital pontocerebellar hypoplasia type 1 (1)
1	-	-	Distal spinal muscular atrophy (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	VRK1-related disorder (1)
-	-	-	Amyotrophic lateral sclerosis;C0026847:Spinal muscular atrophy;C1843504:Pontocerebellar hypoplasia type 1A;C5548369:Neuronopathy, distal hereditary motor, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.18
Sift	Benign	0.22	T
Sift4G	Benign	0.36	T
Polyphen		0.88	P
Vest4		0.49
MutPred		0.55		Gain of catalytic residue at N281 (P = 0.0027)
MVP		0.49
MPC		0.35
ClinPred		0.047	T
GERP RS		4.7
Varity_R		0.29
gMVP		0.65
Mutation Taster		=75/25	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: rs139476915; hg19: chr14-97322892;