4-169561898-TAAAA-TAAAAA

Variant names:

• chr4-169561898-T-TA
• rs398124255
• NM_001199397.3:c.1081-8dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.1081-8dupT variant causes a splice region, 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, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -1.82
• Publications: 1 publications found

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]

NEK1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis, susceptibility to, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• short-rib thoracic dysplasia 6 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome type II

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NEK1	NM_001199397.3	c.1081-8dupT		splice_region_variant, intron_variant	Intron 13 of 35	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6	c.1081-8dupT		splice_region_variant, intron_variant	Intron 13 of 35	1	NM_001199397.3	ENSP00000424757.2

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

GnomAD2 exomes AF: 0.0681 AC: 15532 AN: 228056 AF XY: 0.0672

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 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

African (AFR) AF: 0.161 AC: 5124 AN: 31904

American (AMR) AF: 0.0394 AC: 1616 AN: 41048

Ashkenazi Jewish (ASJ) AF: 0.0782 AC: 1991 AN: 25470

East Asian (EAS) AF: 0.0270 AC: 1064 AN: 39414

South Asian (SAS) AF: 0.0867 AC: 7042 AN: 81234

European-Finnish (FIN) AF: 0.0710 AC: 3760 AN: 52932

Middle Eastern (MID) AF: 0.0515 AC: 287 AN: 5576

European-Non Finnish (NFE) AF: 0.0617 AC: 67953 AN: 1100978

Other (OTH) AF: 0.0697 AC: 4135 AN: 59334

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

African (AFR) AF: 0.159 AC: 6564 AN: 41178

American (AMR) AF: 0.0533 AC: 808 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3468

East Asian (EAS) AF: 0.0287 AC: 148 AN: 5162

South Asian (SAS) AF: 0.0835 AC: 400 AN: 4792

European-Finnish (FIN) AF: 0.0666 AC: 685 AN: 10290

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0623 AC: 4220 AN: 67762

Other (OTH) AF: 0.0738 AC: 154 AN: 2088

Alfa AF: 0.0341 Hom.: 31

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

Apr 11, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short rib-polydactyly syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs398124255; hg19: chr4-170483049; COSMIC: COSV101455976;