rs34540355

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001199397.3(NEK1):c.1388C>T(p.Ala463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,538 control chromosomes in the GnomAD database, including 2,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 152 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2527 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.55

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016297698).

BP6

Variant 4-169555974-G-A is Benign according to our data. Variant chr4-169555974-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 348114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-169555974-G-A is described in Lovd as [Benign]. Variant chr4-169555974-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK1	NM_001199397.3 link	c.1388C>T	p.Ala463Val	missense_variant	Exon 17 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.1388C>T	p.Ala463Val	missense_variant	Exon 17 of 36	1	NM_001199397.3	ENSP00000424757.2		Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5471

AN:

152020

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0198

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0578

Gnomad OTH

AF:

0.0431

GnomAD3 exomes

AF:

0.0358

AC:

8903

AN:

248794

Hom.:

256

AF XY:

0.0366

AC XY:

4944

AN XY:

134978

show subpopulations

Gnomad AFR exome

AF:

0.0101

Gnomad AMR exome

AF:

0.0242

Gnomad ASJ exome

AF:

0.0224

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0581

Gnomad OTH exome

AF:

0.0409

GnomAD4 exome

AF:

0.0546

AC:

79763

AN:

1461400

Hom.:

2527

Cov.:

AF XY:

0.0536

AC XY:

38991

AN XY:

726974

show subpopulations

Gnomad4 AFR exome

AF:

0.00983

Gnomad4 AMR exome

AF:

0.0251

Gnomad4 ASJ exome

AF:

0.0208

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0204

Gnomad4 NFE exome

AF:

0.0650

Gnomad4 OTH exome

AF:

0.0477

GnomAD4 genome

AF:

0.0360

AC:

5473

AN:

152138

Hom.:

152

Cov.:

AF XY:

0.0337

AC XY:

2506

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0406

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.0198

Gnomad4 NFE

AF:

0.0578

Gnomad4 OTH

AF:

0.0427

Alfa

AF:

0.0527

Hom.:

399

Bravo

AF:

0.0372

TwinsUK

AF:

0.0655

AC:

243

ALSPAC

AF:

0.0701

AC:

270

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0572

AC:

470

ExAC

AF:

0.0350

AC:

4224

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not specified

Benign:2

Apr 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Connective tissue disorder

Benign:1

May 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.053

T;.;.;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.76

T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

L;L;L;L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.78

N;N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.24

T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.010

B;.;B;B;B

Vest4

0.063

MPC

0.055

ClinPred

0.0062

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.16

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

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