4-169588719-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001199397.3(NEK1):c.481C>T(p.Arg161*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000517 in 1,547,228 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 Pathogenic,other (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

NEK1
NM_001199397.3 stop_gained

Scores

Clinical Significance

Pathogenic; other criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 4.78

Publications

6 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-169588719-G-A is Pathogenic according to our data. Variant chr4-169588719-G-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 266058.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
NEK1	NM_001199397.3 link	c.481C>T	p.Arg161*	stop_gained	Exon 8 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.481C>T	p.Arg161*	stop_gained	Exon 8 of 36	1	NM_001199397.3	ENSP00000424757.2		Q96PY6-3

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000114

AC:

AN:

158166

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1395086

Hom.:

Cov.:

AF XY:

0.0000683

AC XY:

AN XY:

688444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31520

American (AMR)

AF:

0.0000560

AC:

AN:

35712

Ashkenazi Jewish (ASJ)

AF:

0.00183

AC:

AN:

25132

East Asian (EAS)

AF:

0.00

AC:

AN:

35682

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000140

AC:

AN:

1074988

Other (OTH)

AF:

0.000104

AC:

AN:

57896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41514

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.0000628

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000615

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

NEK1-related disorder

Pathogenic:1

Jun 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NEK1 c.481C>T variant is predicted to result in premature protein termination (p.Arg161*). This variant has been reported in one individual with amyotrophic lateral sclerosis (ALS, Table S4, Black et al. 2016. PubMed ID: 28089114). Protein-truncating variants upstream and downstream of this variant have been reported to be pathogenic (HGMD, ClinVar). However, the c.481C>T variant has been reported in 20 and 80 heterozygous individuals in gnomAD v2 and v4, respectively. Protein-truncating variants in NEK1 are expected to be pathogenic. At this time, we interpret this variant as likely pathogenic. -

Short-rib thoracic dysplasia 6 with or without polydactyly

Pathogenic:1

Apr 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 266058). This premature translational stop signal has been observed in individual(s) with NEK1-related conditions (PMID: 28089114, 29431110). This variant is present in population databases (rs202115635, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Arg161*) 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). For these reasons, this variant has been classified as Pathogenic. -

Motor neuron disease

Other:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance:other

Review Status:criteria provided, single submitter

Collection Method:case-control

Loss-of-function but lacking segregation data Loss-of-function

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

PhyloP100

4.8

Vest4

0.90

GERP RS

5.2

Mutation Taster

=2/198

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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