4-127881151-G-A

Position:

chr4-127881151-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014264.5(PLK4):c.17G>A(p.Gly6Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,614,040 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

PLK4
NM_014264.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008492082).

BP6

Variant 4-127881151-G-A is Benign according to our data. Variant chr4-127881151-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (212/152330) while in subpopulation NFE AF= 0.0021 (143/68024). AF 95% confidence interval is 0.00182. There are 2 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLK4	NM_014264.5 linkuse as main transcript	c.17G>A	p.Gly6Glu	missense_variant	1/16	ENST00000270861.10	NP_055079.3
PLK4	NM_001190799.2 linkuse as main transcript	c.17G>A	p.Gly6Glu	missense_variant	1/15		NP_001177728.1
PLK4	XM_005262701.4 linkuse as main transcript	c.17G>A	p.Gly6Glu	missense_variant	1/16		XP_005262758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLK4	ENST00000270861.10 linkuse as main transcript	c.17G>A	p.Gly6Glu	missense_variant	1/16	1	NM_014264.5	ENSP00000270861	P1	O00444-1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.0451

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00119

AC:

297

AN:

250038

Hom.:

AF XY:

0.00129

AC XY:

175

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00210

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00134

AC:

1952

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1001

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152330

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00210

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PLK4: BS2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 02, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.0085

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.4

L;.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.37

MVP

0.54

MPC

0.55

ClinPred

0.18

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over