chr13-52136897-C-G

Position:

• chr13-52136897-C-G

Variant summary

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

The NM_002498.3(NEK3):​c.933G>C​(p.Glu311Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEK3 NM_002498.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.414

Genes affected

NEK3 (HGNC:7746): (NIMA related kinase 3) This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein differs from other NimA family members in that it is not cell cycle regulated and is found primarily in the cytoplasm. The kinase is activated by prolactin stimulation, leading to phosphorylation of VAV2 guanine nucleotide exchange factor, paxillin, and activation of the RAC1 GTPase. Two functional alleles for this gene have been identified in humans. The reference genome assembly (GRCh38) represents a functional allele that is associated with the inclusion of an additional coding exon in protein-coding transcripts, compared to an alternate functional allele that lacks the exon. [provided by RefSeq, Sep 2019]

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	UniProt
NEK3	NM_002498.3	c.933G>C	p.Glu311Asp	missense_variant	12/16	ENST00000610828.5
NEK3	NM_152720.3	c.933G>C	p.Glu311Asp	missense_variant	12/16
NEK3	NR_164641.1	n.995G>C		non_coding_transcript_exon_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK3	ENST00000610828.5	c.933G>C	p.Glu311Asp	missense_variant	12/16	1	NM_002498.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Jun 04, 2024

The c.933G>C (p.E311D) alteration is located in exon 12 (coding exon 11) of the NEK3 gene. This alteration results from a G to C substitution at nucleotide position 933, causing the glutamic acid (E) at amino acid position 311 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.2
DANN	Benign	0.80
DEOGEN2	Benign	0.0030	.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.66	T;T;T;.
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	.;.;N;N
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.017	.;.;B;B
Vest4		0.092
MVP		0.16
ClinPred		0.017	T
GERP RS		1.2
Varity_R		0.040
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 1

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: chr13-52711033;