3-52763618-G-T

Position:

• chr3-52763618-G-T

Variant summary

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

The NM_003157.6(NEK4):​c.673C>A​(p.Pro225Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NEK4 NM_003157.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.65

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]

ACMG classification

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	c.673C>A	p.Pro225Thr	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	c.673C>A	p.Pro225Thr	missense_variant	5/16	1	NM_003157.6	ENSP00000233027.5
NEK4	ENST00000383721.8	c.673C>A	p.Pro225Thr	missense_variant	5/14	1		ENSP00000373227.4
NEK4	ENST00000535191.5	c.406C>A	p.Pro136Thr	missense_variant	4/15	2		ENSP00000437703.1
NEK4	ENST00000461689.5	c.406C>A	p.Pro136Thr	missense_variant	4/14	5		ENSP00000419666.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432884 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 711018

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Benign	0.076	T;T;D;T
Polyphen		0.96	D;.;P;.
Vest4		0.37
MutPred		0.34		Loss of catalytic residue at P224 (P = 0.0142);.;Loss of catalytic residue at P224 (P = 0.0142);.;
MVP		0.29
MPC		0.66
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.56

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

Other links and lift over

dbSNP: rs1029871; hg19: chr3-52797634;