rs372585344

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001199397.3(NEK1):c.1137T>A(p.Asp379Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,610,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D379G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: -0.00200

Publications

0 publications found

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 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

NEK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020308822).

BP6

Variant 4-169561835-A-T is Benign according to our data. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047. Variant chr4-169561835-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 266047.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK1	NM_001199397.3 link	c.1137T>A	p.Asp379Glu	missense_variant	Exon 14 of 36	ENST00000507142.6	NP_001186326.1	Q96PY6-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6 link	c.1137T>A	p.Asp379Glu	missense_variant	Exon 14 of 36	1	NM_001199397.3	ENSP00000424757.2		Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000138

AC:

AN:

246484

AF XY:

0.000127

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000387

AC:

565

AN:

1458292

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

260

AN XY:

725206

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33378

American (AMR)

AF:

0.0000225

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000487

AC:

541

AN:

1110614

Other (OTH)

AF:

0.000315

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41498

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.000141

AC:

EpiCase

AF:

0.000330

EpiControl

AF:

0.000358

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 20, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28089114) -

Sep 01, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEK1-related disorder

Uncertain:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NEK1 c.1137T>A variant is predicted to result in the amino acid substitution p.Asp379Glu. This variant was reported in a control individual in a study of patients with motor neuron disease; to our knowledge, it has not been reported in any affected individuals (Supplementary Table 4 in Black et al. 2016. PubMed ID: 28089114). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Short-rib thoracic dysplasia 6 with or without polydactyly

Uncertain:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 379 of the NEK1 protein (p.Asp379Glu). This variant is present in population databases (rs372585344, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NEK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 266047). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NEK1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Amyotrophic lateral sclerosis, susceptibility to, 24

Uncertain:1

Oct 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NEK1 c.1137T>A; p.Asp379Glu variant (rs372585344), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 266047). It is observed in the Non-Finnish European population at an overall frequency of 0.027% (34/125486 alleles) in the Genome Aggregation Database. The aspartic acid 379 is highly conserved (Alamut v.2.11), however several species have glutamic acid at this position, suggesting that this amino acid change may be evolutionary tolerated. Further, computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Motor neuron disease

Benign:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.026

T;.;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.66

T;T;T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.020

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

N;N;N;N;N

PhyloP100

-0.0020

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.14

N;N;N;N;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;.;B;B;B

Vest4

0.068

MutPred

0.11

Gain of ubiquitination at K378 (P = 0.1204);Gain of ubiquitination at K378 (P = 0.1204);Gain of ubiquitination at K378 (P = 0.1204);Gain of ubiquitination at K378 (P = 0.1204);Gain of ubiquitination at K378 (P = 0.1204);

MVP

0.40

MPC

0.051

ClinPred

0.022

GERP RS

0.0029

Varity_R

0.026

gMVP

0.050

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over