chr13-52143981-T-G

Variant names:

• chr13-52143981-T-G
• NM_002498.3:c.811A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002498.3(NEK3):​c.811A>C​(p.Met271Leu) 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. 14/19 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: 0.0450
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07552001).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK3	NM_002498.3	MANE Select	c.811A>C	p.Met271Leu	missense	Exon 10 of 16	NP_002489.1	P51956-1
	NEK3	NM_001424264.1		c.829A>C	p.Met277Leu	missense	Exon 10 of 16	NP_001411193.1
	NEK3	NM_001424265.1		c.811A>C	p.Met271Leu	missense	Exon 10 of 16	NP_001411194.1	P51956-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK3	ENST00000610828.5	TSL:1 MANE Select	c.811A>C	p.Met271Leu	missense	Exon 10 of 16	ENSP00000480328.1	P51956-1
	NEK3	ENST00000962649.1		c.829A>C	p.Met277Leu	missense	Exon 9 of 15	ENSP00000632708.1
	NEK3	ENST00000618534.4	TSL:5	c.811A>C	p.Met271Leu	missense	Exon 10 of 16	ENSP00000484443.1	P51956-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.045
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.28
ClinPred		0.057	T
GERP RS		1.7
PromoterAI		-0.0069	Neutral
Varity_R		0.069
gMVP		0.16
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr13-52718116;