chr14-96876033-C-T

Variant names:

• chr14-96876033-C-T
• rs137853063
• NM_003384.3:c.1072C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_003384.3(VRK1):​c.1072C>T​(p.Arg358*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,232 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003761341: "In vitro functional studies provide some evidence that the p.Arg358Ter variant may impact protein function." PMID:25609612, PMID:21920476, PMID:31527692" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R358R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: VRK1 NM_003384.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 0.00600
• Publications: 24 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003761341: "In vitro functional studies provide some evidence that the p.Arg358Ter variant may impact protein function." PMID:25609612, PMID:21920476, PMID:31527692; SCV000263027: Functional studies suggest that this alteration demonstrates mislocalization, reduced protein stability and reduced kinase activity (Martin-Doncel, 2019; Sanz-Garcia, 2011).; SCV000617744: Published functional studies in lymphoblastoid cell lines demonstrate an extreme reduction in the mRNA and protein levels of APP (amyloid-beta precursor protein), which has a role in neuronal migration (Vinograd-Byk et al., 2015)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-96876033-C-T is Pathogenic according to our data. Variant chr14-96876033-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7497.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.1072C>T	p.Arg358*	stop_gained	Exon 12 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.1072C>T	p.Arg358*	stop_gained	Exon 12 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.1069C>T	p.Arg357*	stop_gained splice_region	Exon 12 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.1072C>T	p.Arg358*	stop_gained	Exon 12 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.1072C>T	p.Arg358*	stop_gained	Exon 12 of 14	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000915477.1		c.1072C>T	p.Arg358*	stop_gained	Exon 12 of 14	ENSP00000585536.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000639 AC: 16 AN: 250524 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1460278 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 726528

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

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

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111110

Other (OTH) AF: 0.0000829 AC: 5 AN: 60304

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74200

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Pontocerebellar hypoplasia type 1A (6)
2	-	-	not provided (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Congenital pontocerebellar hypoplasia type 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 10 (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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.64	D
PhyloP100		0.0060
Vest4		0.81
ClinPred		0.93	D
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	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: rs137853063; hg19: chr14-97342370; COSMIC: COSV53708943; COSMIC: COSV53708943;