chr13-52151194-T-A

Variant names:

• chr13-52151194-T-A
• rs1327818663
• NM_002498.3:c.500A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002498.3(NEK3):​c.500A>T​(p.Tyr167Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. Y167C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEK3 NM_002498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

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.500A>T	p.Tyr167Phe	missense	Exon 7 of 16	NP_002489.1	P51956-1
	NEK3	NM_001424264.1		c.518A>T	p.Tyr173Phe	missense	Exon 7 of 16	NP_001411193.1
	NEK3	NM_001424265.1		c.500A>T	p.Tyr167Phe	missense	Exon 7 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.500A>T	p.Tyr167Phe	missense	Exon 7 of 16	ENSP00000480328.1	P51956-1
	NEK3	ENST00000962649.1		c.518A>T	p.Tyr173Phe	missense	Exon 6 of 15	ENSP00000632708.1
	NEK3	ENST00000618534.4	TSL:5	c.500A>T	p.Tyr167Phe	missense	Exon 7 of 16	ENSP00000484443.1	P51956-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Benign	0.78	N
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.048	D
Polyphen		0.97	D
Vest4		0.72
MVP		0.52
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.35
gMVP		0.57
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

dbSNP: rs1327818663; hg19: chr13-52725329;