1-44801630-C-T

Variant names:

• chr1-44801630-C-T
• rs140199593
• NM_004073.4:c.444C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP7 BS2

The NM_004073.4(PLK3):​c.444C>T​(p.Ala148Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A148A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PLK3 NM_004073.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP7: Synonymous conserved (PhyloP=0.096 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.444C>T	p.Ala148Ala	synonymous	Exon 4 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.444C>T	p.Ala148Ala	synonymous	Exon 4 of 15	ENSP00000361275.4	Q9H4B4
	PLK3	ENST00000854219.1		c.444C>T	p.Ala148Ala	synonymous	Exon 4 of 15	ENSP00000524278.1
	PLK3	ENST00000850614.1		c.444C>T	p.Ala148Ala	synonymous	Exon 4 of 15	ENSP00000520901.1	Q9H4B4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461412 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		0.096
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs140199593; hg19: chr1-45267302;