Variant 3-52711859-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003157.6(NEK4):c.2444G>A(p.Arg815Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,591,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NEK4
NM_003157.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.945

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011461616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NEK4	NM_003157.6 linkuse as main transcript	c.2444G>A	p.Arg815Gln	missense_variant	16/16	ENST00000233027.10	NP_003148.2
NEK4	NM_001348412.2 linkuse as main transcript	c.2306G>A	p.Arg769Gln	missense_variant	15/15		NP_001335341.1
NEK4	NM_001348414.2 linkuse as main transcript	c.2198G>A	p.Arg733Gln	missense_variant	16/16		NP_001335343.1
NEK4	NM_001193533.3 linkuse as main transcript	c.2177G>A	p.Arg726Gln	missense_variant	15/15		NP_001180462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK4	ENST00000233027.10 linkuse as main transcript	c.2444G>A	p.Arg815Gln	missense_variant	16/16	1	NM_003157.6	ENSP00000233027.5		P51957-1
NEK4	ENST00000535191.5 linkuse as main transcript	c.2177G>A	p.Arg726Gln	missense_variant	15/15	2		ENSP00000437703.1		P51957-3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

245676

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

133030

show subpopulations

Gnomad AFR exome

AF:

0.000562

Gnomad AMR exome

AF:

0.0000303

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.0000684

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

153

AN:

1438876

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

716794

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.0000458

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.000130

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000265

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.011

DANN

Benign

0.83

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.050

N;.

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.13

Sift

Benign

0.56

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.047

B;.

Vest4

0.066

MVP

0.30

MPC

0.17

ClinPred

0.0090

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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