4-169394015-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001199397.3(NEK1):c.*495T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,320 control chromosomes in the GnomAD database, including 11,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11121 hom., cov: 32)
  • Exomes 𝑓: 0.30 (17 hom.)
• Consequence: NEK1 NM_001199397.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-169394015-A-G is Benign according to our data. Variant chr4-169394015-A-G is described in ClinVar as [Benign]. Clinvar id is 348083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.*495T>C		3_prime_UTR_variant	36/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.*495T>C		3_prime_UTR_variant	36/36	1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56526 AN: 151946 Hom.: 11096 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.346

GnomAD4 exome AF: 0.301 AC: 77 AN: 256 Hom.: 17 Cov.: 0 AF XY: 0.289 AC XY: 44 AN XY: 152

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.372 AC: 56593 AN: 152064 Hom.: 11121 Cov.: 32 AF XY: 0.371 AC XY: 27564 AN XY: 74316

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.0678

Gnomad4 SAS AF: 0.457

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.343

Alfa AF: 0.333 Hom.: 6517

Bravo AF: 0.370

Asia WGS AF: 0.291 AC: 1015 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.82
Cadd	Benign	5.2
Dann	Benign	0.70

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: rs1129694; hg19: chr4-170315166;