3-52711826-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003157.6(NEK4):ā€‹c.2477G>Cā€‹(p.Ser826Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

NEK4
NM_003157.6 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29762232).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEK4NM_003157.6 linkc.2477G>C p.Ser826Thr missense_variant 16/16 ENST00000233027.10 NP_003148.2
NEK4NM_001348412.2 linkc.2339G>C p.Ser780Thr missense_variant 15/15 NP_001335341.1
NEK4NM_001348414.2 linkc.2231G>C p.Ser744Thr missense_variant 16/16 NP_001335343.1
NEK4NM_001193533.3 linkc.2210G>C p.Ser737Thr missense_variant 15/15 NP_001180462.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEK4ENST00000233027.10 linkc.2477G>C p.Ser826Thr missense_variant 16/161 NM_003157.6 ENSP00000233027.5 P51957-1
NEK4ENST00000535191.5 linkc.2210G>C p.Ser737Thr missense_variant 15/152 ENSP00000437703.1 P51957-3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1458914
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725830
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

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 submitterclinical testingAmbry GeneticsNov 12, 2024The c.2477G>C (p.S826T) alteration is located in exon 16 (coding exon 16) of the NEK4 gene. This alteration results from a G to C substitution at nucleotide position 2477, causing the serine (S) at amino acid position 826 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
-0.036
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.019
T;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.79
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.30
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
2.0
M;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.23
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.032
D;D
Polyphen
0.92
P;.
Vest4
0.33
MutPred
0.27
Gain of phosphorylation at S826 (P = 0.0522);.;
MVP
0.71
MPC
0.36
ClinPred
0.91
D
GERP RS
4.7
Varity_R
0.20
gMVP
0.25

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.

Other links and lift over

dbSNP: rs1228358452; hg19: chr3-52745842; API