chr14-96833480-T-G

Variant names:

• chr14-96833480-T-G
• rs771646609
• NM_003384.3:c.9T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_003384.3(VRK1):​c.9T>G​(p.Arg3Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,240 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VRK1 NM_003384.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 14-96833480-T-G is Benign according to our data. Variant chr14-96833480-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1106863.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.06 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.9T>G	p.Arg3Arg	synonymous	Exon 2 of 13	NP_003375.1	Q99986
	VRK1	NM_001411051.1		c.9T>G	p.Arg3Arg	synonymous	Exon 2 of 14	NP_001397980.1	H0YJF7
	VRK1	NM_001411053.1		c.9T>G	p.Arg3Arg	synonymous	Exon 2 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.9T>G	p.Arg3Arg	synonymous	Exon 2 of 13	ENSP00000216639.3	Q99986
	VRK1	ENST00000679770.1		c.9T>G	p.Arg3Arg	synonymous	Exon 2 of 14	ENSP00000505214.1	A0A7P0Z445
	VRK1	ENST00000679462.1		c.9T>G	p.Arg3Arg	synonymous	Exon 1 of 12	ENSP00000506011.1	A0A7P0TAA6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250962 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461240 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726938

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111626

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pontocerebellar hypoplasia type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.8
DANN	Benign	0.77
PhyloP100		1.1
PromoterAI		-0.027	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: rs771646609; hg19: chr14-97299817;