Variant 3-52741450-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003157.6(NEK4):c.2054C>T(p.Thr685Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000754 in 1,458,600 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: 6.98

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEK4	NM_003157.6 linkuse as main transcript	c.2054C>T	p.Thr685Ile	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.2054C>T	p.Thr685Ile	missense_variant	13/16	1	NM_003157.6	ENSP00000233027.5	P51957-1
NEK4	ENST00000383721.8 linkuse as main transcript	c.1916C>T	p.Thr639Ile	missense_variant	12/14	1		ENSP00000373227.4	P51957-2
NEK4	ENST00000535191.5 linkuse as main transcript	c.1787C>T	p.Thr596Ile	missense_variant	12/15	2		ENSP00000437703.1	P51957-3
NEK4	ENST00000461689.5 linkuse as main transcript	c.1787C>T	p.Thr596Ile	missense_variant	12/14	5		ENSP00000419666.1	E7EX48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251360

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458600

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725836

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000811

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Jun 05, 2023

The c.2054C>T (p.T685I) alteration is located in exon 13 (coding exon 13) of the NEK4 gene. This alteration results from a C to T substitution at nucleotide position 2054, causing the threonine (T) at amino acid position 685 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

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.042

D;D;D;D

Polyphen

0.99

D;.;D;.

Vest4

0.51

MutPred

0.11

Loss of glycosylation at T685 (P = 0.0182);.;.;.;

MVP

0.93

MPC

0.47

ClinPred

0.99

GERP RS

5.8

Varity_R

0.33

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.38

Position offset: -39

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