4-169394345-C-T

Position:

• chr4-169394345-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.*165G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 517,018 control chromosomes in the GnomAD database, including 207,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63310 hom., cov: 32)
  • Exomes 𝑓: 0.89 (144233 hom.)
• Consequence: NEK1 NM_001199397.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.567

Genes affected

NEK1 (HGNC:7744): (NIMA related kinase 1) The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-169394345-C-T is Benign according to our data. Variant chr4-169394345-C-T is described in ClinVar as [Benign]. Clinvar id is 348085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-169394345-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.*165G>A		3_prime_UTR_variant	36/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.*165G>A		3_prime_UTR_variant	36/36	1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes AF: 0.911 AC: 138534 AN: 152086 Hom.: 63253 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.918

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.929

Gnomad NFE AF: 0.880

Gnomad OTH AF: 0.878

GnomAD4 exome AF: 0.888 AC: 324089 AN: 364814 Hom.: 144233 Cov.: 4 AF XY: 0.889 AC XY: 171049 AN XY: 192420

Gnomad4 AFR exome AF: 0.966

Gnomad4 AMR exome AF: 0.931

Gnomad4 ASJ exome AF: 0.883

Gnomad4 EAS exome AF: 0.843

Gnomad4 SAS exome AF: 0.913

Gnomad4 FIN exome AF: 0.915

Gnomad4 NFE exome AF: 0.881

Gnomad4 OTH exome AF: 0.888

GnomAD4 genome AF: 0.911 AC: 138649 AN: 152204 Hom.: 63310 Cov.: 32 AF XY: 0.913 AC XY: 67978 AN XY: 74416

Gnomad4 AFR AF: 0.971

Gnomad4 AMR AF: 0.925

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.818

Gnomad4 SAS AF: 0.918

Gnomad4 FIN AF: 0.910

Gnomad4 NFE AF: 0.880

Gnomad4 OTH AF: 0.879

Alfa AF: 0.896 Hom.: 15187

Bravo AF: 0.913

Asia WGS AF: 0.857 AC: 2973 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

- -

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.072
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs4692721; hg19: chr4-170315496;