Variant 3-52763618-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003157.6(NEK4):c.673C>G(p.Pro225Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,580,566 control chromosomes in the GnomAD database, including 115,006 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.33 ( 9539 hom., cov: 33)

Exomes 𝑓: 0.38 ( 105467 hom. )

Consequence

NEK4
NM_003157.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.65

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037811697).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK4	NM_003157.6 linkuse as main transcript	c.673C>G	p.Pro225Ala	missense_variant	5/16	ENST00000233027.10	NP_003148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK4	ENST00000233027.10 linkuse as main transcript	c.673C>G	p.Pro225Ala	missense_variant	5/16	1	NM_003157.6	ENSP00000233027	P2	P51957-1
NEK4	ENST00000383721.8 linkuse as main transcript	c.673C>G	p.Pro225Ala	missense_variant	5/14	1		ENSP00000373227	A2	P51957-2
NEK4	ENST00000535191.5 linkuse as main transcript	c.406C>G	p.Pro136Ala	missense_variant	4/15	2		ENSP00000437703		P51957-3
NEK4	ENST00000461689.5 linkuse as main transcript	c.406C>G	p.Pro136Ala	missense_variant	4/14	5		ENSP00000419666

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50482

AN:

151970

Hom.:

9536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.458

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.390

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.357

GnomAD3 exomes

AF:

0.381

AC:

88991

AN:

233464

Hom.:

18241

AF XY:

0.374

AC XY:

47196

AN XY:

126234

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.529

Gnomad ASJ exome

AF:

0.452

Gnomad EAS exome

AF:

0.425

Gnomad SAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.401

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.378

AC:

539399

AN:

1428478

Hom.:

105467

Cov.:

AF XY:

0.373

AC XY:

264182

AN XY:

708988

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.511

Gnomad4 ASJ exome

AF:

0.460

Gnomad4 EAS exome

AF:

0.477

Gnomad4 SAS exome

AF:

0.206

Gnomad4 FIN exome

AF:

0.401

Gnomad4 NFE exome

AF:

0.387

Gnomad4 OTH exome

AF:

0.358

GnomAD4 genome

AF:

0.332

AC:

50504

AN:

152088

Hom.:

9539

Cov.:

AF XY:

0.334

AC XY:

24826

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.154

Gnomad4 AMR

AF:

0.458

Gnomad4 ASJ

AF:

0.450

Gnomad4 EAS

AF:

0.427

Gnomad4 SAS

AF:

0.208

Gnomad4 FIN

AF:

0.390

Gnomad4 NFE

AF:

0.396

Gnomad4 OTH

AF:

0.362

Alfa

AF:

0.391

Hom.:

9142

Bravo

AF:

0.332

TwinsUK

AF:

0.375

AC:

1390

ALSPAC

AF:

0.384

AC:

1479

ESP6500AA

AF:

0.152

AC:

668

ESP6500EA

AF:

0.403

AC:

3469

ExAC

AF:

0.372

AC:

45123

Asia WGS

AF:

0.330

AC:

1146

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

L;.;L;.

MutationTaster

Benign

0.0000013

P;P;P

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Benign

0.099

T;T;T;T

Polyphen

0.88

P;.;P;.

Vest4

0.20

MPC

0.46

ClinPred

0.022

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.48

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over