rs3736901

Positions:

• chr10-94284977-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016341.4(PLCE1):​c.5035+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,389,412 control chromosomes in the GnomAD database, including 95,281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8085 hom., cov: 32)
  • Exomes 𝑓: 0.37 (87196 hom.)
• Consequence: PLCE1 NM_016341.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.14

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-94284977-C-A is Benign according to our data. Variant chr10-94284977-C-A is described in ClinVar as [Benign]. Clinvar id is 260722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94284977-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.5035+12C>A		intron_variant		ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.5035+12C>A		intron_variant		1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43924 AN: 151882 Hom.: 8073 Cov.: 32

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.353 AC: 87480 AN: 247582 Hom.: 17534 AF XY: 0.348 AC XY: 46710 AN XY: 134344

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.526

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.368 AC: 455205 AN: 1237412 Hom.: 87196 Cov.: 18 AF XY: 0.363 AC XY: 228023 AN XY: 627404

Gnomad4 AFR exome AF: 0.0592

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.289 AC: 43948 AN: 152000 Hom.: 8085 Cov.: 32 AF XY: 0.295 AC XY: 21910 AN XY: 74288

Gnomad4 AFR AF: 0.0705

Gnomad4 AMR AF: 0.432

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.281

Alfa AF: 0.347 Hom.: 13967

Bravo AF: 0.276

Asia WGS AF: 0.197 AC: 682 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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, 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	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 63% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 59. Only high quality variants are reported. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs3736901; hg19: chr10-96044734; COSMIC: COSV53343096;