rs199947197

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001199397.3(NEK1):ā€‹c.3107C>Gā€‹(p.Ser1036*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,613,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.00022 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-169424668-G-C is Pathogenic according to our data. Variant chr4-169424668-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEK1NM_001199397.3 linkc.3107C>G p.Ser1036* stop_gained Exon 31 of 36 ENST00000507142.6 NP_001186326.1 Q96PY6-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEK1ENST00000507142.6 linkc.3107C>G p.Ser1036* stop_gained Exon 31 of 36 1 NM_001199397.3 ENSP00000424757.2 Q96PY6-3

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000124
AC:
31
AN:
249026
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135072
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000275
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000222
AC:
324
AN:
1461486
Hom.:
0
Cov.:
31
AF XY:
0.000226
AC XY:
164
AN XY:
727006
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.00
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:
0.000284
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000203
Hom.:
0
Bravo
AF:
0.000128
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000366
AC:
3
ExAC
AF:
0.000116
AC:
14
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:6
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1008*) in the NEK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEK1 are known to be pathogenic (PMID: 22499340, 29068549). This variant is present in population databases (rs199947197, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of short rib-polydactyly syndrome and/or amyotrophic lateral sclerosis (PMID: 26945885, 28123176, 28935222, 29068549). This variant is also known as c.3107C>G (p.S1036*). ClinVar contains an entry for this variant (Variation ID: 208600). For these reasons, this variant has been classified as Pathogenic. -

Dec 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Ser1036X variant in NEK1 has not been previously reported in the literature, but other variants leading to loss of function of the NEK1 protein have been reported in individuals with autosomal recessive short-rib polydactyly syndrome (Thiel 2011, Hokayem 2012). This variant has been identified in 0.04% (3/8196) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199947197). Other predicted loss of function variants in NEK1 gene are also rare in the general population, consistent with a pathogenic role. This nonsense variant leads to a premature termination codon at position 1036, which is predicted to lead to a truncated or absent protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser1036X variant is likely pathogenic for short-rib polydactyly syndrome in an autosomal recessive manner based on the predicted impact on protein function. -

-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Dec 07, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2017
Dan Cohn Lab, University Of California Los Angeles
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 18, 2018
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:4
Jun 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 19, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NEK1 c.3023C>G; p.Ser1008Ter variant (rs199947197), also known as c.3107C>G; p.Ser1036Ter for NM_001199397.1, is reported in the literature in the compound heterozygous state with other pathogenic NEK1 variants in individuals affected with short rib-polydactyly syndrome II or axial spondylometaphyseal dysplasia (Wang 2017, Zhang 2018). This variant is reported in ClinVar (Variation ID: 208600), and is found in the general population with an overall allele frequency of 0.012% (33/280416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Wang Z et al. Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. J Hum Genet. 2017 Apr;62(4):503-506. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -

Feb 11, 2025
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported using alternate nomenclature p.(S1036X) as a risk allele for familial ALS but further research is needed to understand this association (PMID: 26945885); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Also known as c.3107C>G p.(S1036*); This variant is associated with the following publications: (PMID: 32920598, 28935222, 29068549, 34582081, 32409511, 35896380, 26945885, 37159497, 38849340, 37849306, 39222049, 28123176) -

Short-rib thoracic dysplasia 6 with or without polydactyly;C4693523:Amyotrophic lateral sclerosis, susceptibility to, 24 Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

NEK1-related disorder Pathogenic:1
Sep 16, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The NEK1 c.3023C>G variant is predicted to result in premature protein termination (p.Ser1008*). This variant, also described as c.3107C>G (p.Ser1036*), has been reported in the compound heterozygous state in individuals with axial spondylometaphyseal dysplasia and short rib dysplasia (Wang et al. 2017. PubMed ID: 28123176; table S2, Zhang et al. 2017. PubMed ID: 29068549). This variant has also been reported in two brothers with amyotrophic lateral sclerosis (ALS) as well as in an unrelated control; however, the brothers also carried an expanded C9orf72 allele that is likely the most penetrant variant (Nguyen et al. 2017. PubMed ID: 28935222). Additionally, this variant was present in an affected brother and an unaffected brother indicating this variant exhibits incomplete penetrance, which is commonly observed in NEK1 protein-truncating variants (Brenner et al. 2016. PubMed ID: 26945885). This variant has been interpreted as pathogenic and likely pathogenic in ClinVar. Internally, we have reported this variant in multiple individuals undergoing ALS testing as well as finding this variant in the compound heterozygous state in an individual with phenotypic features consistent with short-rib polydactyly. Taken together, we classify this variant as likely pathogenic. -

Amyotrophic lateral sclerosis, susceptibility to, 24 Other:1
Feb 28, 2018
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Benign
0.74
D
Vest4
0.86
GERP RS
1.8

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: rs199947197; hg19: chr4-170345819; API