rs371295780

Variant names:

• chr14-96847326-A-G
• rs371295780
• NM_003384.3:c.356A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP3 PP5_Very_Strong

The NM_003384.3(VRK1):​c.356A>G​(p.His119Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001588881: Experimental studies have shown that this missense change affects VRK1 function (PMID:31527692)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: VRK1 NM_003384.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.82
• Publications: 10 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001588881: Experimental studies have shown that this missense change affects VRK1 function (PMID: 31527692).; SCV000618460: Published functional studies demonstrate reduced kinase activity (Martin-Doncel et al., 2019)
• 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 14-96847326-A-G is Pathogenic according to our data. Variant chr14-96847326-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 209204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.356A>G	p.His119Arg	missense	Exon 5 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.356A>G	p.His119Arg	missense	Exon 5 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.356A>G	p.His119Arg	missense	Exon 5 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.356A>G	p.His119Arg	missense	Exon 5 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.356A>G	p.His119Arg	missense	Exon 5 of 14	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000679462.1		c.356A>G	p.His119Arg	missense	Exon 4 of 12	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251168 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461376 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.000112 AC: 5 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111640

Other (OTH) AF: 0.0000663 AC: 4 AN: 60376

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Pontocerebellar hypoplasia type 1A (3)
1	-	-	not provided (1)
1	-	-	Pontocerebellar hypoplasia type 1A;C5882703:Neuronopathy, distal hereditary motor, autosomal recessive 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.082	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.81
MVP		0.86
MPC		0.97
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.78
gMVP		0.84
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs371295780; hg19: chr14-97313663;