rs377607698

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001199397.3(NEK1):​c.3140C>T​(p.Ser1047Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000558 in 1,613,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1047S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 missense

Scores

2
14
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 5.49
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-169424635-G-A is Pathogenic according to our data. Variant chr4-169424635-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 266054.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEK1NM_001199397.3 linkuse as main transcriptc.3140C>T p.Ser1047Leu missense_variant 31/36 ENST00000507142.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEK1ENST00000507142.6 linkuse as main transcriptc.3140C>T p.Ser1047Leu missense_variant 31/361 NM_001199397.3 A2Q96PY6-3

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
248950
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
135024
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000582
AC:
85
AN:
1461360
Hom.:
0
Cov.:
31
AF XY:
0.0000537
AC XY:
39
AN XY:
726912
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000747
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000340
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000268
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Motor neuron disease Pathogenic:1
Likely pathogenic, criteria provided, single submittercase-controlCentre for Genomic and Experimental Medicine, University of EdinburghAug 31, 2016- -
Short-rib thoracic dysplasia 6 with or without polydactyly Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1019 of the NEK1 protein (p.Ser1019Leu). This variant is present in population databases (rs377607698, gnomAD 0.008%). This missense change has been observed in individual(s) with NEK1-related conditions (PMID: 28089114). This variant is also known as c.C3140T; p.S1047L. ClinVar contains an entry for this variant (Variation ID: 266054). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NEK1 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.017
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.45
T;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.60
D;D;D;D;D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.6
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.2
D;D;D;D;D
REVEL
Uncertain
0.42
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0
D;.;D;D;D
Vest4
0.49
MVP
0.95
MPC
0.27
ClinPred
0.90
D
GERP RS
5.6
Varity_R
0.23
gMVP
0.32

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.

Other links and lift over

dbSNP: rs377607698; hg19: chr4-170345786; COSMIC: COSV71456917; API