chr4-169587562-ATGTT-A

Variant names:

• chr4-169587562-ATGTT-A
• rs1554075284
• NM_001199397.3:c.599_602delAACA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001199397.3(NEK1):​c.599_602delAACA​(p.Lys200MetfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,340,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: NEK1 NM_001199397.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 4-169587562-ATGTT-A is Pathogenic according to our data. Variant chr4-169587562-ATGTT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446668.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199397.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 9 of 36	NP_001186326.1
	NEK1	NM_001374418.1		c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 8 of 35	NP_001361347.1
	NEK1	NM_001374419.1		c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 9 of 35	NP_001361348.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 9 of 36	ENSP00000424757.2
	NEK1	ENST00000439128.6	TSL:1	c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 8 of 34	ENSP00000408020.2
	NEK1	ENST00000511633.5	TSL:1	c.599_602delAACA	p.Lys200MetfsTer8	frameshift	Exon 9 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340582 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 663932

African (AFR) AF: 0.00 AC: 0 AN: 28970

American (AMR) AF: 0.00 AC: 0 AN: 31374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24272

East Asian (EAS) AF: 0.00 AC: 0 AN: 35002

South Asian (SAS) AF: 0.00 AC: 0 AN: 69486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 9.62e-7 AC: 1 AN: 1040018

Other (OTH) AF: 0.00 AC: 0 AN: 55672

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554075284; hg19: chr4-170508713;