Variant 3-52739603-C-T 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.2125G>A(p.Val709Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NEK4
NM_003157.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.72

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=0.21024007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK4	NM_003157.6 linkuse as main transcript	c.2125G>A	p.Val709Ile	missense_variant	14/16	ENST00000233027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK4	ENST00000233027.10 linkuse as main transcript	c.2125G>A	p.Val709Ile	missense_variant	14/16	1	NM_003157.6	P2	P51957-1
NEK4	ENST00000383721.8 linkuse as main transcript	c.1987G>A	p.Val663Ile	missense_variant	13/14	1		A2	P51957-2
NEK4	ENST00000535191.5 linkuse as main transcript	c.1858G>A	p.Val620Ile	missense_variant	13/15	2			P51957-3
NEK4	ENST00000461689.5 linkuse as main transcript	c.1858G>A	p.Val620Ile	missense_variant	13/14	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Nov 08, 2021

The c.2125G>A (p.V709I) alteration is located in exon 14 (coding exon 14) of the NEK4 gene. This alteration results from a G to A substitution at nucleotide position 2125, causing the valine (V) at amino acid position 709 to be replaced by an isoleucine (I). 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

0.18

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.;.;T

Eigen

Benign

0.035

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.8

L;.;.;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.45

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.057

T;T;T;T

Sift4G

Benign

0.084

T;T;T;D

Polyphen

0.041

B;.;B;.

Vest4

0.21

MutPred

0.25

Loss of disorder (P = 0.1719);.;.;.;

MVP

0.55

MPC

0.15

ClinPred

0.47

GERP RS

4.2

Varity_R

0.037

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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