1-44800536-G-A

Variant names:

• chr1-44800536-G-A
• rs1241305978
• NM_004073.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004073.4(PLK3):​c.73G>A​(p.Gly25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,314,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: PLK3 NM_004073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16106737).

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.73G>A	p.Gly25Arg	missense	Exon 1 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.73G>A	p.Gly25Arg	missense	Exon 1 of 15	ENSP00000361275.4	Q9H4B4
	PLK3	ENST00000854219.1		c.73G>A	p.Gly25Arg	missense	Exon 1 of 15	ENSP00000524278.1
	PLK3	ENST00000850614.1		c.73G>A	p.Gly25Arg	missense	Exon 1 of 15	ENSP00000520901.1	Q9H4B4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000228 AC: 3 AN: 1314628 Hom.: 0 Cov.: 32 AF XY: 0.00000154 AC XY: 1 AN XY: 648234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26332

American (AMR) AF: 0.00 AC: 0 AN: 23528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22906

East Asian (EAS) AF: 0.00 AC: 0 AN: 28410

South Asian (SAS) AF: 0.00 AC: 0 AN: 71674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1049164

Other (OTH) AF: 0.00 AC: 0 AN: 54478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0482410), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.17	N
REVEL	Benign	0.067
Sift	Uncertain	0.025	D
Sift4G	Benign	0.34	T
Polyphen		0.0050	B
Vest4		0.23
MutPred		0.21		Gain of methylation at G25 (P = 0.0222)
MVP		0.57
MPC		0.47
ClinPred		0.12	T
GERP RS		0.075
PromoterAI		0.085	Neutral
Varity_R		0.094
gMVP		0.42
Mutation Taster		=96/4	polymorphism

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: rs1241305978; hg19: chr1-45266208;