NM_014264.5:c.52C>T

Variant names:

• chr4-127881852-C-T
• rs751605196
• NM_014264.5:c.52C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014264.5(PLK4):​c.52C>T​(p.Leu18Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. L18I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLK4 NM_014264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27
• Publications: 0 publications found

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]

PLK4 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014264.5. 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
	PLK4	NM_014264.5	MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 2 of 16	NP_055079.3
	PLK4	NM_001441357.1		c.55C>T	p.Leu19Phe	missense	Exon 2 of 16	NP_001428286.1
	PLK4	NM_001190799.2		c.52C>T	p.Leu18Phe	missense	Exon 2 of 15	NP_001177728.1	O00444-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK4	ENST00000270861.10	TSL:1 MANE Select	c.52C>T	p.Leu18Phe	missense	Exon 2 of 16	ENSP00000270861.5	O00444-1
	PLK4	ENST00000513090.5	TSL:2	c.52C>T	p.Leu18Phe	missense	Exon 2 of 15	ENSP00000427554.1	O00444-2
	PLK4	ENST00000852980.1		c.52C>T	p.Leu18Phe	missense	Exon 2 of 16	ENSP00000523039.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.095	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		5.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.80		Gain of sheet (P = 0.0827)
MVP		0.58
MPC		0.51
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.65
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs751605196; hg19: chr4-128803007;