Genetic Variant PLK4:p.Ile5Phe (chr4-127881147-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014264.5(PLK4):c.13A>T(p.Ile5Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I5V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLK4
NM_014264.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.74

Publications

0 publications found

Variant links:

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

PLK4 links:

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ACMG classification

Classification was made for transcript

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=0.14108407).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLK4	NM_014264.5	MANE Select	c.13A>T	p.Ile5Phe	missense	Exon 1 of 16	NP_055079.3
PLK4	NM_001190799.2		c.13A>T	p.Ile5Phe	missense	Exon 1 of 15	NP_001177728.1	O00444-2
PLK4	NM_001441359.1		c.13A>T	p.Ile5Phe	missense	Exon 1 of 16	NP_001428288.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLK4	ENST00000270861.10	TSL:1 MANE Select	c.13A>T	p.Ile5Phe	missense	Exon 1 of 16	ENSP00000270861.5	O00444-1
PLK4	ENST00000513090.5	TSL:2	c.13A>T	p.Ile5Phe	missense	Exon 1 of 15	ENSP00000427554.1	O00444-2
PLK4	ENST00000852980.1		c.13A>T	p.Ile5Phe	missense	Exon 1 of 16	ENSP00000523039.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.099

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.84

M_CAP

Benign

0.015

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.23

PhyloP100

3.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.060

REVEL

Benign

0.16

Sift

Benign

0.43

Sift4G

Benign

0.60

Polyphen

0.011

Vest4

0.32

MutPred

0.34

Loss of catalytic residue at I5 (P = 0.0339)

MVP

0.51

MPC

0.50

ClinPred

0.59

GERP RS

3.1

PromoterAI

-0.040

Neutral

(source)

Varity_R

0.51

gMVP

0.31

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over