rs34540355

Positions:

• chr4-169555974-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.1388C>T​(p.Ala463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,538 control chromosomes in the GnomAD database, including 2,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (152 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2527 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.55

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016297698).
• BP6: Variant 4-169555974-G-A is Benign according to our data. Variant chr4-169555974-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 348114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-169555974-G-A is described in Lovd as [Benign]. Variant chr4-169555974-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK1	NM_001199397.3	c.1388C>T	p.Ala463Val	missense_variant	17/36	ENST00000507142.6	NP_001186326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK1	ENST00000507142.6	c.1388C>T	p.Ala463Val	missense_variant	17/36	1	NM_001199397.3	ENSP00000424757.2

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5471 AN: 152020 Hom.: 152 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0358 AC: 8903 AN: 248794 Hom.: 256 AF XY: 0.0366 AC XY: 4944 AN XY: 134978

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0546 AC: 79763 AN: 1461400 Hom.: 2527 Cov.: 32 AF XY: 0.0536 AC XY: 38991 AN XY: 726974

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0477

GnomAD4 genome AF: 0.0360 AC: 5473 AN: 152138 Hom.: 152 Cov.: 32 AF XY: 0.0337 AC XY: 2506 AN XY: 74384

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.0578

Gnomad4 OTH AF: 0.0427

Alfa AF: 0.0527 Hom.: 399

Bravo AF: 0.0372

TwinsUK AF: 0.0655 AC: 243

ALSPAC AF: 0.0701 AC: 270

ESP6500AA AF: 0.0102 AC: 38

ESP6500EA AF: 0.0572 AC: 470

ExAC AF: 0.0350 AC: 4224

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.76	T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L;L;L;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N;N;N;N;N
REVEL	Benign	0.091
Sift	Benign	0.24	T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.010	B;.;B;B;B
Vest4		0.063
MPC		0.055
ClinPred		0.0062	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.16

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

Other links and lift over

dbSNP: rs34540355; hg19: chr4-170477125;