4-127881145-G-A

Position:

• chr4-127881145-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014264.5(PLK4):​c.11G>A​(p.Cys4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLK4 NM_014264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

Genes affected

PLK4 (HGNC:11397): (polo like kinase 4) This gene encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles, complex microtubule-based structures found in centrosomes, and regulates centriole duplication during the cell cycle. Three alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072630525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLK4	NM_014264.5	c.11G>A	p.Cys4Tyr	missense_variant	1/16	ENST00000270861.10	NP_055079.3
PLK4	NM_001190799.2	c.11G>A	p.Cys4Tyr	missense_variant	1/15		NP_001177728.1
PLK4	XM_005262701.4	c.11G>A	p.Cys4Tyr	missense_variant	1/16		XP_005262758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLK4	ENST00000270861.10	c.11G>A	p.Cys4Tyr	missense_variant	1/16	1	NM_014264.5	ENSP00000270861	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 4 of the PLK4 protein (p.Cys4Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2115440). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;.;N;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.61	N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.18
MutPred		0.31		Gain of disorder (P = 0.0471);Gain of disorder (P = 0.0471);Gain of disorder (P = 0.0471);Gain of disorder (P = 0.0471);
MVP		0.12
MPC		0.16
ClinPred		0.28	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.49

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-128802300;