rs141639885

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_016341.4(PLCE1):c.1729G>A(p.Ala577Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,614,182 control chromosomes in the GnomAD database, including 11 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 0.0042 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 6 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 6.74

Variant links:

Genes affected

PLCE1 (HGNC:17175): (phospholipase C epsilon 1) This gene encodes a phospholipase enzyme that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers subsequently regulate various processes affecting cell growth, differentiation, and gene expression. This enzyme is regulated by small monomeric GTPases of the Ras and Rho families and by heterotrimeric G proteins. In addition to its phospholipase C catalytic activity, this enzyme has an N-terminal domain with guanine nucleotide exchange (GEF) activity. Mutations in this gene cause early-onset nephrotic syndrome; characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]

PLCE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCE1. . Gene score misZ 1.381 (greater than the threshold 3.09). Trascript score misZ 3.1046 (greater than threshold 3.09). GenCC has associacion of gene with nephrotic syndrome, type 3, familial idiopathic steroid-resistant nephrotic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.007831275).

BP6

Variant 10-94171416-G-A is Benign according to our data. Variant chr10-94171416-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260713.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00418 (636/152316) while in subpopulation AFR AF= 0.0132 (549/41578). AF 95% confidence interval is 0.0123. There are 5 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.1729G>A	p.Ala577Thr	missense_variant	4/33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8 linkuse as main transcript	c.1729G>A	p.Ala577Thr	missense_variant	4/33	1	NM_016341.4	ENSP00000360431	P1	Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.00418

AC:

636

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00115

AC:

286

AN:

249376

Hom.:

AF XY:

0.000835

AC XY:

113

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000407

AC:

595

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

249

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

Gnomad4 AMR exome

AF:

0.00186

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.000993

GnomAD4 genome

AF:

0.00418

AC:

636

AN:

152316

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0132

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000755

Hom.:

Bravo

AF:

0.00509

ESP6500AA

AF:

0.0140

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2018	- -

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 13, 2017

- -

Nephrotic syndrome, type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;.

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.82

N;N;N

REVEL

Benign

0.078

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.081

T;T;T

Polyphen

0.57

P;P;P

Vest4

0.36

MVP

0.58

MPC

0.11

ClinPred

0.023

GERP RS

5.8

Varity_R

0.16

gMVP

0.33

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