1-44801685-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_004073.4(PLK3):​c.499C>T​(p.Arg167Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,610,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R167Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PLK3
NM_004073.4 missense

Scores

4
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.751
BS2
High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLK3NM_004073.4 linkc.499C>T p.Arg167Trp missense_variant 4/15 ENST00000372201.5 NP_004064.2 Q9H4B4
PLK3XM_047444455.1 linkc.499C>T p.Arg167Trp missense_variant 4/13 XP_047300411.1
PLK3XM_047444463.1 linkc.499C>T p.Arg167Trp missense_variant 4/9 XP_047300419.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLK3ENST00000372201.5 linkc.499C>T p.Arg167Trp missense_variant 4/151 NM_004073.4 ENSP00000361275.4 Q9H4B4
PLK3ENST00000465443.5 linkn.575C>T non_coding_transcript_exon_variant 4/145
PLK3ENST00000476731.1 linkn.52C>T non_coding_transcript_exon_variant 1/55

Frequencies

GnomAD3 genomes
AF:
0.00000665
AC:
1
AN:
150486
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251280
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1460366
Hom.:
0
Cov.:
36
AF XY:
0.0000289
AC XY:
21
AN XY:
726492
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000665
AC:
1
AN:
150486
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
73388
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2024The c.499C>T (p.R167W) alteration is located in exon 4 (coding exon 4) of the PLK3 gene. This alteration results from a C to T substitution at nucleotide position 499, causing the arginine (R) at amino acid position 167 to be replaced by a tryptophan (W). 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
0.14
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.42
T
Eigen
Benign
0.038
Eigen_PC
Benign
-0.042
FATHMM_MKL
Benign
0.67
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.057
D
MetaRNN
Pathogenic
0.75
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.64
MutPred
0.70
Loss of MoRF binding (P = 0.057);
MVP
0.63
MPC
1.2
ClinPred
0.84
D
GERP RS
0.41
Varity_R
0.45
gMVP
0.73

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779797606; hg19: chr1-45267357; COSMIC: COSV99043046; COSMIC: COSV99043046; API