4-169561898-TA-TAA

Position:

• chr4-169561898-TA-TAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.1081-8_1081-7insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,588,998 control chromosomes in the GnomAD database, including 4,075 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (755 hom., cov: 30)
  • Exomes 𝑓: 0.065 (3320 hom.)
• Consequence: NEK1 NM_001199397.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -1.82

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 -16 ACMG points.

• BP6: Variant 4-169561898-T-TA is Benign according to our data. Variant chr4-169561898-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 95506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.1081-8_1081-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.1081-8_1081-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13298 AN: 150992 Hom.: 753 Cov.: 30

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0286

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.0666

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0623

Gnomad OTH AF: 0.0745

GnomAD3 exomes AF: 0.0681 AC: 15532 AN: 228056 Hom.: 605 AF XY: 0.0672 AC XY: 8342 AN XY: 124178

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0802

Gnomad EAS exome AF: 0.0258

Gnomad SAS exome AF: 0.0863

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0647 AC: 92972 AN: 1437890 Hom.: 3320 Cov.: 30 AF XY: 0.0645 AC XY: 46134 AN XY: 715006

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0394

Gnomad4 ASJ exome AF: 0.0782

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.0867

Gnomad4 FIN exome AF: 0.0710

Gnomad4 NFE exome AF: 0.0617

Gnomad4 OTH exome AF: 0.0697

GnomAD4 genome AF: 0.0881 AC: 13312 AN: 151108 Hom.: 755 Cov.: 30 AF XY: 0.0881 AC XY: 6500 AN XY: 73812

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0533

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.0287

Gnomad4 SAS AF: 0.0835

Gnomad4 FIN AF: 0.0666

Gnomad4 NFE AF: 0.0623

Gnomad4 OTH AF: 0.0738

Bravo AF: 0.0910

Asia WGS AF: 0.0640 AC: 221 AN: 3446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Short rib-polydactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs398124255; hg19: chr4-170483049;