14-96833516-A-T

Variant names:

• chr14-96833516-A-T
• rs2145635
• NM_003384.3:c.45A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003384.3(VRK1):​c.45A>T​(p.Ala15Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VRK1 NM_003384.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.762
• Publications: 20 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), G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=-0.762 with no splicing effect.

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.45A>T	p.Ala15Ala	synonymous	Exon 2 of 13	NP_003375.1
	VRK1	NM_001411051.1		c.45A>T	p.Ala15Ala	synonymous	Exon 2 of 14	NP_001397980.1
	VRK1	NM_001411053.1		c.45A>T	p.Ala15Ala	synonymous	Exon 2 of 13	NP_001397982.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VRK1	ENST00000216639.8	TSL:1 MANE Select	c.45A>T	p.Ala15Ala	synonymous	Exon 2 of 13	ENSP00000216639.3
	VRK1	ENST00000679770.1		c.45A>T	p.Ala15Ala	synonymous	Exon 2 of 14	ENSP00000505214.1
	VRK1	ENST00000679462.1		c.45A>T	p.Ala15Ala	synonymous	Exon 1 of 12	ENSP00000506011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.41
PhyloP100		-0.76
PromoterAI		0.0074	Neutral

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: rs2145635; hg19: chr14-97299853;