10-94306584-A-G

Position:

chr10-94306584-A-G

Variant summary

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

The NM_016341.4(PLCE1):c.5780A>G(p.His1927Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,668 control chromosomes in the GnomAD database, including 74,193 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7401 hom., cov: 32)

Exomes 𝑓: 0.30 ( 66792 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.06

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 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=0.004501492).

BP6

Variant 10-94306584-A-G is Benign according to our data. Variant chr10-94306584-A-G is described in ClinVar as [Benign]. Clinvar id is 260728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94306584-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.5780A>G	p.His1927Arg	missense_variant	26/33	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.5780A>G	p.His1927Arg	missense_variant	26/33	1	NM_016341.4	ENSP00000360431	P1	Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47158

AN:

151938

Hom.:

7385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.210

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.330

GnomAD3 exomes

AF:

0.282

AC:

70230

AN:

249328

Hom.:

10567

AF XY:

0.287

AC XY:

38888

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.350

Gnomad AMR exome

AF:

0.169

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.229

Gnomad SAS exome

AF:

0.283

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.310

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.299

AC:

436911

AN:

1461612

Hom.:

66792

Cov.:

AF XY:

0.301

AC XY:

218919

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.354

Gnomad4 AMR exome

AF:

0.179

Gnomad4 ASJ exome

AF:

0.434

Gnomad4 EAS exome

AF:

0.236

Gnomad4 SAS exome

AF:

0.283

Gnomad4 FIN exome

AF:

0.226

Gnomad4 NFE exome

AF:

0.304

Gnomad4 OTH exome

AF:

0.315

GnomAD4 genome

AF:

0.310

AC:

47199

AN:

152056

Hom.:

7401

Cov.:

AF XY:

0.304

AC XY:

22575

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.346

Gnomad4 AMR

AF:

0.252

Gnomad4 ASJ

AF:

0.450

Gnomad4 EAS

AF:

0.229

Gnomad4 SAS

AF:

0.281

Gnomad4 FIN

AF:

0.210

Gnomad4 NFE

AF:

0.317

Gnomad4 OTH

AF:

0.328

Alfa

AF:

0.322

Hom.:

17558

Bravo

AF:

0.313

TwinsUK

AF:

0.309

AC:

1147

ALSPAC

AF:

0.293

AC:

1130

ESP6500AA

AF:

0.334

AC:

1345

ESP6500EA

AF:

0.311

AC:

2596

ExAC

AF:

0.284

AC:

34369

Asia WGS

AF:

0.289

AC:

1003

AN:

3478

EpiCase

AF:

0.332

EpiControl

AF:

0.332

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Benign:3

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 35% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 33. Only high quality variants are reported. -
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+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 24116107, 25139097, 22203178, 20729852, 23826241, 22412849, 20729853, 24127316, 23688607) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign

0.045

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.43

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.18

T;T;.

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.95

N;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.43

PROVEAN

Benign

2.6

N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.046

MPC

0.57

ClinPred

0.0027

GERP RS

5.4

Varity_R

0.068

gMVP

0.15

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