10-94171330-G-T

Position:

chr10-94171330-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_016341.4(PLCE1):c.1643G>T(p.Arg548Leu) variant causes a missense change. The variant allele was found at a frequency of 0.175 in 1,613,912 control chromosomes in the GnomAD database, including 26,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.17 ( 2389 hom., cov: 32)

Exomes 𝑓: 0.18 ( 23934 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.76

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 -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, PLCE1

BP4

Computational evidence support a benign effect (MetaRNN=0.0017680526).

BP6

Variant 10-94171330-G-T is Benign according to our data. Variant chr10-94171330-G-T is described in ClinVar as [Benign]. Clinvar id is 260712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94171330-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.1643G>T	p.Arg548Leu	missense_variant	4/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8 linkuse as main transcript	c.1643G>T	p.Arg548Leu	missense_variant	4/33	1	NM_016341.4	P1	Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26145

AN:

151978

Hom.:

2384

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.178

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.172

AC:

42951

AN:

249426

Hom.:

4355

AF XY:

0.182

AC XY:

24656

AN XY:

135306

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.0932

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.112

Gnomad SAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.176

AC:

256581

AN:

1461814

Hom.:

23934

Cov.:

AF XY:

0.180

AC XY:

130640

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.0976

Gnomad4 ASJ exome

AF:

0.215

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.310

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.181

GnomAD4 genome

AF:

0.172

AC:

26162

AN:

152098

Hom.:

2389

Cov.:

AF XY:

0.171

AC XY:

12727

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.189

Gnomad4 AMR

AF:

0.146

Gnomad4 ASJ

AF:

0.215

Gnomad4 EAS

AF:

0.129

Gnomad4 SAS

AF:

0.326

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.174

Alfa

AF:

0.162

Hom.:

3387

Bravo

AF:

0.171

TwinsUK

AF:

0.169

AC:

628

ALSPAC

AF:

0.163

AC:

630

ESP6500AA

AF:

0.174

AC:

711

ESP6500EA

AF:

0.170

AC:

1427

ExAC

AF:

0.178

AC:

21525

EpiCase

AF:

0.178

EpiControl

AF:

0.183

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

Nephrotic syndrome, type 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	This variant is associated with the following publications: (PMID: 25060053, 31013750) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2017	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;.

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

0.016

P;P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.086

Sift

Benign

0.047

D;T;T

Sift4G

Uncertain

0.051

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.30

MPC

0.51

ClinPred

0.011

GERP RS

4.9

Varity_R

0.12

gMVP

0.55

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