14-96881177-G-A

Variant names:

• chr14-96881177-G-A
• rs1420939606
• NM_003384.3:c.1160G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000742630: 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" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R387C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: VRK1 NM_003384.3 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.94
• Publications: 5 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000742630: 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).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 14-96881177-G-A is Pathogenic according to our data. Variant chr14-96881177-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521856.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.1160G>A	p.Arg387His	missense splice_region	Exon 13 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.1232G>A	p.Ser411Asn	missense splice_region	Exon 14 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.1157G>A	p.Arg386His	missense splice_region	Exon 13 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.1160G>A	p.Arg387His	missense splice_region	Exon 13 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000915477.1		c.1253G>A	p.Gly418Asp	missense	Exon 14 of 14	ENSP00000585536.1
	VRK1	ENST00000680683.1		c.1181G>A	p.Gly394Asp	missense	Exon 13 of 13	ENSP00000506334.1	A0A7P0TAS8

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000913 AC: 22 AN: 240850 AF XY: 0.0000846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000624

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: 0.000169

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1452970 Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 12 AN XY: 722064

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.000522 AC: 23 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00 AC: 0 AN: 84682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5534

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107266

Other (OTH) AF: 0.0000500 AC: 3 AN: 59996

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74272

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00197 AC: 30 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000249

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 10 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)
1	-	-	Pontocerebellar hypoplasia type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.0070
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.076
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.33		Gain of helix (P = 0.0078)
MVP		0.43
MPC		0.34
ClinPred		0.094	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.44
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 0

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

Other links and lift over

dbSNP: rs1420939606; hg19: chr14-97347514;