rs199947197

Variant summary

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

The NM_001199397.3(NEK1):c.3107C>G(p.Ser1036Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 stop_gained

Scores

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]

NEK1 links:

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/exons	MANE	UniProt
NEK1	NM_001199397.3 linkuse as main transcript	c.3107C>G	p.Ser1036Ter	stop_gained	31/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6 linkuse as main transcript	c.3107C>G	p.Ser1036Ter	stop_gained	31/36	1	NM_001199397.3	A2	Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152120

Hom.:

Cov.:

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:

AN:

249026

Hom.:

AF XY:

0.000111

AC XY:

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.:

Cov.:

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:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

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.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000366

AC:

ExAC

AF:

0.000116

AC:

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 24, 2014	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 208600). This variant is also known as c.3107C>G (p.S1036). 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 present in population databases (rs199947197, gnomAD 0.03%). 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). -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2020	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 18, 2018	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	Reported using alternate nomenclature p.(S1036X) as a risk allele for familial ALS but further research is needed to understand this association (Brenner et al., 2016); 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; This variant is associated with the following publications: (PMID: 32920598, 28935222, 29068549, 34582081, 32409511, 35896380, 26945885, 28123176) -

Short-rib thoracic dysplasia 6 with or without polydactyly;C4693523:Amyotrophic lateral sclerosis, susceptibility to, 24

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

NEK1-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

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). The c.3023C>G variant has also been reported in three ALS cases. In one report the c.3023C>G variant was found in two brothers with ALS but also in an unrelated control; the brothers also harbored an expanded C9orf72 allele that may be the most penetrant variant (Nguyen et al. 2017. PubMed ID: 28935222). In a second study the c.3023C>G variant was present in an affected brother and an unaffected older brother indicating this variant exhibits incomplete penetrance (Brenner et al. 2016. PubMed ID: 26945885). The c.3023C>G variant has been interpreted as pathogenic and likely pathogenic in ClinVar. At PreventionGenetics, 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 (internal data). Together we classify the c.3023C>G variant as likely pathogenic for autosomal recessive skeletal dysplasia as well as an increased susceptibility to ALS. -

Amyotrophic lateral sclerosis, susceptibility to, 24

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.29

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.74

MutationTaster

Benign

1.0

A;A;A;A;A

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.

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