NM_003384.3:c.-6+145T>C

Variant names:

• chr14-96797592-T-C
• rs71419296
• NM_003384.3:c.-6+145T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003384.3(VRK1):​c.-6+145T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 151,538 control chromosomes in the GnomAD database, including 29,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (29472 hom., cov: 32)
  • Exomes 𝑓: 0.63 (7 hom.)
• Consequence: VRK1 NM_003384.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.50
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-96797592-T-C is Benign according to our data. Variant chr14-96797592-T-C is described in ClinVar as [Benign]. Clinvar id is 1251145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VRK1	NM_003384.3	c.-6+145T>C		intron_variant	Intron 1 of 12	ENST00000216639.8	NP_003375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VRK1	ENST00000216639.8	c.-6+145T>C		intron_variant	Intron 1 of 12	1	NM_003384.3	ENSP00000216639.3

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93205 AN: 151394 Hom.: 29456 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.632 AC: 24 AN: 38 Hom.: 7 AF XY: 0.647 AC XY: 22 AN XY: 34

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 24 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.616 AC: 93252 AN: 151500 Hom.: 29472 Cov.: 32 AF XY: 0.612 AC XY: 45326 AN XY: 74006

African (AFR) AF: 0.661 AC: 27375 AN: 41386

American (AMR) AF: 0.524 AC: 7974 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2073 AN: 3472

East Asian (EAS) AF: 0.156 AC: 790 AN: 5060

South Asian (SAS) AF: 0.612 AC: 2951 AN: 4818

European-Finnish (FIN) AF: 0.608 AC: 6358 AN: 10458

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.645 AC: 43727 AN: 67768

Other (OTH) AF: 0.600 AC: 1264 AN: 2108

Alfa AF: 0.631 Hom.: 3790

Bravo AF: 0.608

Asia WGS AF: 0.424 AC: 1468 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.22
PhyloP100		-1.5
PromoterAI		0.12	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs71419296; hg19: chr14-97263929;