1-44801721-C-T

Position:

chr1-44801721-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004073.4(PLK3):c.535C>T(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,545,818 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R179R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00089 ( 2 hom. )

Consequence

PLK3
NM_004073.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552

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]

PLK3 links:

PLK3 (HGNC:):

PLK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06807071).

BS2

High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLK3	NM_004073.4 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	4/15	ENST00000372201.5	NP_004064.2	Q9H4B4
PLK3	XM_047444455.1 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	4/13		XP_047300411.1
PLK3	XM_047444463.1 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	4/9		XP_047300419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLK3	ENST00000372201.5 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	4/15	1	NM_004073.4	ENSP00000361275.4	Q9H4B4
PLK3	ENST00000465443.5 linkuse as main transcript	n.611C>T		non_coding_transcript_exon_variant	4/14	5
PLK3	ENST00000476731.1 linkuse as main transcript	n.88C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes

AF:

0.000438

AC:

AN:

143786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000348

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:

0.000746

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000485

AC:

122

AN:

251338

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000854

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000892

AC:

1251

AN:

1401916

Hom.:

Cov.:

AF XY:

0.000836

AC XY:

582

AN XY:

696220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000943

Gnomad4 AMR exome

AF:

0.000747

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.000105

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000602

GnomAD4 genome

AF:

0.000438

AC:

AN:

143902

Hom.:

Cov.:

AF XY:

0.000529

AC XY:

AN XY:

69962

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.000347

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000746

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000730

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.00107

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 submitter

clinical testing

Ambry Genetics

Oct 26, 2024

The c.535C>T (p.R179C) 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 535, causing the arginine (R) at amino acid position 179 to be replaced by a cysteine (C). 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

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.071

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.19

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.076

Vest4

0.55

MVP

0.68

MPC

1.3

ClinPred

0.078

GERP RS

0.25

Varity_R

0.44

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over