rs180753337

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_016341.4(PLCE1):c.3518C>T(p.Ser1173Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000743 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.12

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, PLCE1

BP4

Computational evidence support a benign effect (MetaRNN=0.07616392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.3518C>T	p.Ser1173Phe	missense_variant	11/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8 linkuse as main transcript	c.3518C>T	p.Ser1173Phe	missense_variant	11/33	1	NM_016341.4	P1	Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

249018

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000710

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000828

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 01, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the PLCE1 protein (p.Ser1173Phe). This variant is present in population databases (rs180753337, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PLCE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 586320). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLCE1 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed on the same allele (in cis) with a second variant in a patient with focal segmental glomerulosclerosis in published literature (Lowik et al., 2008); This variant is associated with the following publications: (PMID: 18443213) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The c.3518C>T (p.S1173F) alteration is located in exon 11 (coding exon 10) of the PLCE1 gene. This alteration results from a C to T substitution at nucleotide position 3518, causing the serine (S) at amino acid position 1173 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nephrotic syndrome, type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.0033

BayesDel_noAF

Uncertain

-0.010

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

0.57

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

N;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.45

MVP

0.65

MPC

0.10

ClinPred

0.30

GERP RS

5.0

Varity_R

0.46

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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