chr10-94298541-C-T

Variant names:

• chr10-94298541-C-T
• rs3765524
• NM_016341.4:c.5330C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016341.4(PLCE1):​c.5330C>T​(p.Thr1777Ile) variant causes a missense change. The variant allele was found at a frequency of 0.277 in 1,613,514 control chromosomes in the GnomAD database, including 64,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1777A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7705 hom., cov: 31)
  • Exomes 𝑓: 0.27 (56343 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.13
• Publications: 116 publications found

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 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.8240037E-4).
• BP6: Variant 10-94298541-C-T is Benign according to our data. Variant chr10-94298541-C-T is described in ClinVar as Benign. ClinVar VariationId is 260724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.5330C>T	p.Thr1777Ile	missense_variant	Exon 24 of 33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.5330C>T	p.Thr1777Ile	missense_variant	Exon 24 of 33	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47289 AN: 151664 Hom.: 7685 Cov.: 31

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.267 AC: 66545 AN: 249386 AF XY: 0.271

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.273 AC: 398957 AN: 1461732 Hom.: 56343 Cov.: 36 AF XY: 0.275 AC XY: 200008 AN XY: 727180

African (AFR) AF: 0.426 AC: 14269 AN: 33476

American (AMR) AF: 0.174 AC: 7787 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11039 AN: 26136

East Asian (EAS) AF: 0.235 AC: 9313 AN: 39696

South Asian (SAS) AF: 0.263 AC: 22665 AN: 86256

European-Finnish (FIN) AF: 0.206 AC: 11015 AN: 53420

Middle Eastern (MID) AF: 0.435 AC: 2506 AN: 5766

European-Non Finnish (NFE) AF: 0.272 AC: 302416 AN: 1111866

Other (OTH) AF: 0.297 AC: 17947 AN: 60392

GnomAD4 genome AF: 0.312 AC: 47341 AN: 151782 Hom.: 7705 Cov.: 31 AF XY: 0.305 AC XY: 22649 AN XY: 74160

African (AFR) AF: 0.413 AC: 17052 AN: 41326

American (AMR) AF: 0.250 AC: 3816 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1527 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5166

South Asian (SAS) AF: 0.259 AC: 1243 AN: 4806

European-Finnish (FIN) AF: 0.192 AC: 2023 AN: 10532

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19392 AN: 67922

Other (OTH) AF: 0.330 AC: 698 AN: 2112

Alfa AF: 0.294 Hom.: 24593

Bravo AF: 0.318

TwinsUK AF: 0.276 AC: 1024

ALSPAC AF: 0.257 AC: 991

ESP6500AA AF: 0.394 AC: 1593

ESP6500EA AF: 0.286 AC: 2378

ExAC AF: 0.271 AC: 32743

Asia WGS AF: 0.283 AC: 983 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.306

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:4

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25139097, 20729852) -

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 31. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.033
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.29
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.50	T;T;.
MetaRNN	Benign	0.00078	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	3.8	N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.079
MPC		0.50
ClinPred		0.0052	T
GERP RS		5.6
Varity_R		0.069
gMVP		0.37
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3765524; hg19: chr10-96058298; COSMIC: COSV53339317;