14-96881177-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_003384.3(VRK1):c.1160G>A(p.Arg387His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000361 in 1,605,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
VRK1
NM_003384.3 missense, splice_region
NM_003384.3 missense, splice_region
Scores
3
16
Splicing: ADA: 0.9990
2
Clinical Significance
Conservation
PhyloP100: 3.94
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-96881177-G-A is Pathogenic according to our data. Variant chr14-96881177-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152070Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000913 AC: 22AN: 240850Hom.: 0 AF XY: 0.0000846 AC XY: 11AN XY: 130044
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GnomAD4 exome AF: 0.0000193 AC: 28AN: 1452970Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 12AN XY: 722064
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GnomAD4 genome AF: 0.000197 AC: 30AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74272
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The p.R387H variant (also known as c.1160G>A) is located in coding exon 12 of the VRK1 gene. The arginine at codon 387 is replaced by histidine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 12. This variant has been previously reported in the homozygous state in 2 unrelated patients of Moroccan Jewish descent with adult-onset distal hereditary motor neuropathy (Greenbaum L et al. Muscle Nerve, 2020 Mar;61:395-400). Functional studies show reduced protein interactions with nucleosomes and slightly reduced localization to metaphase plate in vitro (Budziszewski GR et al. Nucleic Acids Res, 2022 May;50:4355-4371). Based on internal structural analysis, R387H disrupts a motif critical to nucleosome-binding (Shin J et al. J Biol Chem, 2011 Jun;286:22131-8; Yokobori K et al. Biosci Rep, 2020 Apr;40; Campillo-Marcos I et al. Cancer Lett, 2021 Apr;503:117-128; Budziszewski GR et al. Nucleic Acids Res, 2022 May;50:4355-4371). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2023 | - - |
Neuronopathy, distal hereditary motor, autosomal recessive 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 24, 2023 | - - |
Pontocerebellar hypoplasia type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 12, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 387 of the VRK1 protein (p.Arg387His). This variant is present in population databases (no rsID available, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of spinal muscular atrophy/distal motor neuropathy (PMID: 31837156; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 521856). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of helix (P = 0.0078);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at