1-44801674-G-T

Position:

• chr1-44801674-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004073.4(PLK3):​c.488G>T​(p.Arg163Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: PLK3 NM_004073.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.18

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]

PLK3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4168891).
• BS2: High AC in GnomAd4 at 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLK3	NM_004073.4	c.488G>T	p.Arg163Leu	missense_variant	4/15	ENST00000372201.5	NP_004064.2
PLK3	XM_047444455.1	c.488G>T	p.Arg163Leu	missense_variant	4/13		XP_047300411.1
PLK3	XM_047444463.1	c.488G>T	p.Arg163Leu	missense_variant	4/9		XP_047300419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLK3	ENST00000372201.5	c.488G>T	p.Arg163Leu	missense_variant	4/15	1	NM_004073.4	ENSP00000361275.4
PLK3	ENST00000465443.5	n.564G>T		non_coding_transcript_exon_variant	4/14	5
PLK3	ENST00000476731.1	n.41G>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.000731 AC: 111 AN: 151864 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000665 AC: 167 AN: 251210 Hom.: 0 AF XY: 0.000640 AC XY: 87 AN XY: 135878

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00124 AC: 1819 AN: 1461714 Hom.: 1 Cov.: 36 AF XY: 0.00119 AC XY: 863 AN XY: 727162

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000730 AC: 111 AN: 151982 Hom.: 0 Cov.: 29 AF XY: 0.000741 AC XY: 55 AN XY: 74266

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00107

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

Jul 22, 2024

The c.488G>T (p.R163L) alteration is located in exon 4 (coding exon 4) of the PLK3 gene. This alteration results from a G to T substitution at nucleotide position 488, causing the arginine (R) at amino acid position 163 to be replaced by a leucine (L). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.35	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.77
MPC		1.4
ClinPred		0.20	T
GERP RS		4.9
Varity_R		0.85
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142872152; hg19: chr1-45267346;