Variant 3-52741459-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003157.6(NEK4):c.2045G>C(p.Ser682Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000754 in 1,458,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NEK4
NM_003157.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

Variant links:

Genes affected

NEK4 (HGNC:11399): (NIMA related kinase 4) The protein encoded by this gene is a serine/threonine protein kinase required for normal entry into replicative senescence. The encoded protein also is involved in cell cycle arrest in response to double-stranded DNA damage. Finally, this protein plays a role in maintaining cilium integrity, and defects in this gene have been associated with ciliopathies. [provided by RefSeq, Jan 2017]

NEK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22868478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK4	NM_003157.6 linkuse as main transcript	c.2045G>C	p.Ser682Thr	missense_variant	13/16	ENST00000233027.10	NP_003148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEK4	ENST00000233027.10 linkuse as main transcript	c.2045G>C	p.Ser682Thr	missense_variant	13/16	1	NM_003157.6	ENSP00000233027.5	P51957-1
NEK4	ENST00000383721.8 linkuse as main transcript	c.1907G>C	p.Ser636Thr	missense_variant	12/14	1		ENSP00000373227.4	P51957-2
NEK4	ENST00000535191.5 linkuse as main transcript	c.1778G>C	p.Ser593Thr	missense_variant	12/15	2		ENSP00000437703.1	P51957-3
NEK4	ENST00000461689.5 linkuse as main transcript	c.1778G>C	p.Ser593Thr	missense_variant	12/14	5		ENSP00000419666.1	E7EX48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251358

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135842

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458734

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2022

The c.2045G>C (p.S682T) alteration is located in exon 13 (coding exon 13) of the NEK4 gene. This alteration results from a G to C substitution at nucleotide position 2045, causing the serine (S) at amino acid position 682 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;.;.;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T;D;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.8

M;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.99

D;.;D;.

Vest4

0.35

MutPred

0.12

Loss of phosphorylation at S682 (P = 0.0253);.;.;.;

MVP

0.84

MPC

0.56

ClinPred

0.46

GERP RS

5.2

Varity_R

0.25

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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