rs483352907

Positions:

• chr4-169537833-A-AT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001199397.3(NEK1):​c.1640dupA​(p.Asn547fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK1 NM_001199397.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.26

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 4-169537833-A-AT is Pathogenic according to our data. Variant chr4-169537833-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30430.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK1	NM_001199397.3	c.1640dupA	p.Asn547fs	frameshift_variant	19/36	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6	c.1640dupA	p.Asn547fs	frameshift_variant	19/36	1	NM_001199397.3	ENSP00000424757.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

NEK1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

The NEK1 c.1640dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn547Lysfs*2). This variant has not been reported in amyotrophic lateral sclerosis. However, it was reported in an individual with short rib-polydactyly syndrome in the absence of a second variant in NEK1 (see family 3, Thiel et al. 2011. PubMed ID: 21211617). In this family, another variant in the gene, DYN2CH1, was also proposed to contribute to the ciliopathy phenotype suggesting the possibility of digenic inheritance. This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in NEK1 are expected to be pathogenic; however, they are known to display incomplete penetrance. This variant is interpreted as likely pathogenic. -

Asphyxiating thoracic dystrophy 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 07, 2011

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs483352907; hg19: chr4-170458984;