NM_004073.4:c.512C>G

Variant names:

• chr1-44801698-C-G
• rs985432770
• NM_004073.4:c.512C>G

Variant summary

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

The NM_004073.4(PLK3):​c.512C>G​(p.Ser171Cys) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: PLK3 NM_004073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

Genes affected

PLK3 (HGNC:2154): (polo like kinase 3) The protein encoded by this gene is a member of the highly conserved polo-like kinase family of serine/threonine kinases. Members of this family are characterized by an amino-terminal kinase domain and a carboxy-terminal bipartite polo box domain that functions as a substrate-binding motif and a cellular localization signal. Polo-like kinases are important regulators of cell cycle progression. This gene has also been implicated in stress responses and double-strand break repair. In human cell lines, this protein is reported to associate with centrosomes in a microtubule-dependent manner, and during mitosis, the protein becomes localized to the mitotic apparatus. Expression of a kinase-defective mutant results in abnormal cell morphology caused by changes in microtubule dynamics and mitotic arrest followed by apoptosis. [provided by RefSeq, Sep 2015]

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, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004073.4. 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
	PLK3	NM_004073.4	MANE Select	c.512C>G	p.Ser171Cys	missense	Exon 4 of 15	NP_004064.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK3	ENST00000372201.5	TSL:1 MANE Select	c.512C>G	p.Ser171Cys	missense	Exon 4 of 15	ENSP00000361275.4	Q9H4B4
	PLK3	ENST00000854219.1		c.512C>G	p.Ser171Cys	missense	Exon 4 of 15	ENSP00000524278.1
	PLK3	ENST00000850614.1		c.512C>G	p.Ser171Cys	missense	Exon 4 of 15	ENSP00000520901.1	Q9H4B4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

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	0.066
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.63		Loss of catalytic residue at S171 (P = 0.0515)
MVP		0.93
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.48
Mutation Taster		=33/67	disease causing

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

dbSNP: rs985432770; hg19: chr1-45267370;