rs189186475

Positions:

chr4-169562196-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001199397.3(NEK1):c.1021G>A(p.Ala341Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,527,934 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 8 hom. )

Consequence

NEK1
NM_001199397.3 missense, splice_region

Scores

Splicing: ADA: 0.4484

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 1.28

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074309707).

BP6

Variant 4-169562196-C-T is Benign according to our data. Variant chr4-169562196-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266046.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK1	NM_001199397.3 linkuse as main transcript	c.1021G>A	p.Ala341Thr	missense_variant, splice_region_variant	13/36	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6 linkuse as main transcript	c.1021G>A	p.Ala341Thr	missense_variant, splice_region_variant	13/36	1	NM_001199397.3	ENSP00000424757	A2	Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

326

AN:

151676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000774

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000788

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00440

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00167

AC:

248

AN:

148168

Hom.:

AF XY:

0.00136

AC XY:

106

AN XY:

78166

show subpopulations

Gnomad AFR exome

AF:

0.000641

Gnomad AMR exome

AF:

0.000932

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00306

AC:

4217

AN:

1376142

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2028

AN XY:

678660

show subpopulations

Gnomad4 AFR exome

AF:

0.000430

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000136

Gnomad4 FIN exome

AF:

0.00264

Gnomad4 NFE exome

AF:

0.00364

Gnomad4 OTH exome

AF:

0.00251

GnomAD4 genome

AF:

0.00215

AC:

326

AN:

151792

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74158

show subpopulations

Gnomad4 AFR

AF:

0.000772

Gnomad4 AMR

AF:

0.000787

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00440

Gnomad4 NFE

AF:

0.00337

Gnomad4 OTH

AF:

0.00333

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000284

AC:

ESP6500EA

AF:

0.00236

AC:

ExAC

AF:

0.000717

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2020	This variant is associated with the following publications: (PMID: 28935222, 28089114, 30755392) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2020	The NEK1 c.1021G>A; p.Ala341Thr variant (rs189186475) has not been reported in the medical literature to be associated with a skeletal dysplasia. However, it has been reported in individuals with motor neuron disease and amyotrophic lateral sclerosis, and also in healthy controls (Black 2016, Nguyen 2018). Furthermore, this variant has been reported to co-occur with a pathogenic TARDBP variant in a patient with motor neuron disease (Black 2016). The p.Ala341Thr variant is listed in ClinVar (Variation ID: 266046), and is observed in the general population with an overall allele frequency of 0.17% (310/179350 alleles) in the Genome Aggregation Database. The alanine at position 341 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: tolerated) predict conflicting effects of this variant on protein structure/function. This variant is also located adjacent to the exon-intron junction, but splicing algorithms (Alamut 2.11) are inconclusive on the variant's impact on the nearby canonical splice acceptor site. Due to limited information, the clinical significance of the p.Ala341Thr variant is uncertain at this time. References: Black H et al. Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017; 51:178.e11-178.e20. Nguyen HP et al. NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients. Neurobiol Aging. 2018 Jan;61:255.e1-255.e7. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NEK1: BP4 -

Short-rib thoracic dysplasia 6 with or without polydactyly

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 09, 2016

- -

Cough;C0021051:Immunodeficiency;C0024312:Lymphopenia;C0344697:Cor triatriatum dexter

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Motor neuron disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

- -

NEK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;.;.;.

Eigen

Benign

0.0031

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

T;T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.037

D;D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D;D

Polyphen

0.13

B;.;B;B;B

Vest4

0.067

MVP

0.67

MPC

0.078

ClinPred

0.012

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.45

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over