3-52739575-A-G

Position:

• chr3-52739575-A-G

Variant summary

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

The NM_003157.6(NEK4):​c.2153T>C​(p.Leu718Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK4 NM_003157.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52

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.2153T>C	p.Leu718Pro	missense_variant	14/16	ENST00000233027.10	NP_003148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEK4	ENST00000233027.10	c.2153T>C	p.Leu718Pro	missense_variant	14/16	1	NM_003157.6	ENSP00000233027.5
NEK4	ENST00000383721.8	c.2015T>C	p.Leu672Pro	missense_variant	13/14	1		ENSP00000373227.4
NEK4	ENST00000535191.5	c.1886T>C	p.Leu629Pro	missense_variant	13/15	2		ENSP00000437703.1
NEK4	ENST00000461689.5	c.1886T>C	p.Leu629Pro	missense_variant	13/14	5		ENSP00000419666.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.2153T>C (p.L718P) alteration is located in exon 14 (coding exon 14) of the NEK4 gene. This alteration results from a T to C substitution at nucleotide position 2153, causing the leucine (L) at amino acid position 718 to be replaced by a proline (P). 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.042	T;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.6	M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.57
MutPred		0.40		Gain of disorder (P = 0.0298);.;.;.;
MVP		0.89
MPC		0.77
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.56
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52773591;