1-44801686-G-A

Variant names:

• chr1-44801686-G-A
• rs1651835377
• NM_004073.4:c.500G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004073.4(PLK3):​c.500G>A​(p.Arg167Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLK3 NM_004073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLK3	NM_004073.4	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 15	ENST00000372201.5	NP_004064.2
PLK3	XM_047444455.1	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 13		XP_047300411.1
PLK3	XM_047444463.1	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 9		XP_047300419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLK3	ENST00000372201.5	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 15	1	NM_004073.4	ENSP00000361275.4
PLK3	ENST00000465443.5	n.576G>A		non_coding_transcript_exon_variant	Exon 4 of 14	5
PLK3	ENST00000476731.1	n.53G>A		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461746 Hom.: 0 Cov.: 36 AF XY: 0.0000124 AC XY: 9 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500G>A (p.R167Q) alteration is located in exon 4 (coding exon 4) of the PLK3 gene. This alteration results from a G to A substitution at nucleotide position 500, causing the arginine (R) at amino acid position 167 to be replaced by a glutamine (Q). 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	0.088
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.94	P
Vest4		0.59
MVP		0.61
MPC		0.95
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1651835377; hg19: chr1-45267358; COSMIC: COSV59499782; COSMIC: COSV59499782;