Genetic Variant VRK1:c.1159+1G>A (chr14-96876121-G-A) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_003384.3(VRK1):c.1159+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000479 in 1,461,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001216818: Studies have shown that disruption of this splice site results in insertion of a 35 bp fragment upstream of exon 13 and introduces a new termination codon (PMID:31560180)." and additional evidence is available in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

VRK1
NM_003384.3 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.30

Publications

1 publications found

Variant links:

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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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

VRK1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003384.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.9, offset of 35, new splice context is: tagGTaaac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001216818: Studies have shown that disruption of this splice site results in insertion of a 35 bp fragment upstream of exon 13 and introduces a new termination codon (PMID: 31560180).; SCV005874338: Transcript analysis from the affected individuals with lower motor neuron diseases with biallelic variant c.1159+1G>A in VRK1 using blood sample showed insertion of a 35 bp fragment from the exon/intron boundary on the 3’ side upstream of exon 13 indicating inefficient RNA splicing of exon 12 and leading to shift in the frame and premature termination (Sedghi M et al., 2019).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-96876121-G-A is Pathogenic according to our data. Variant chr14-96876121-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 848771.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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VRK1	NM_003384.3	MANE Select	c.1159+1G>A	splice_donor intron	N/A	NP_003375.1	Q99986
VRK1	NM_001411051.1		c.1159+1G>A	splice_donor intron	N/A	NP_001397980.1	H0YJF7
VRK1	NM_001411053.1		c.1156+1G>A	splice_donor intron	N/A	NP_001397982.1	A0A7P0T838

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VRK1	ENST00000216639.8	TSL:1 MANE Select	c.1159+1G>A		splice_donor intron	N/A	ENSP00000216639.3	Q99986
VRK1	ENST00000681419.1		c.1160G>A	p.Arg387His	missense	Exon 12 of 12	ENSP00000505512.1	A0A7P0T952
VRK1	ENST00000679770.1		c.1159+1G>A		splice_donor intron	N/A	ENSP00000505214.1	A0A7P0Z445

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251294

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461022

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111420

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 1A (2)

Neuronopathy, distal hereditary motor, autosomal recessive 10 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.91

PhyloP100

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: 34

DS_DL_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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VRK1 p.Arg387His

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over