chr10-94284977-C-A

Variant names:

• chr10-94284977-C-A
• rs3736901
• NM_016341.4:c.5035+12C>A

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.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
• Publications: 9 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-AS1 (HGNC:45193): (PLCE1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 260722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.5035+12C>A		intron_variant	Intron 22 of 32	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.5035+12C>A		intron_variant	Intron 22 of 32	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

GnomAD2 exomes AF: 0.353 AC: 87480 AN: 247582 AF XY: 0.348

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 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

African (AFR) AF: 0.0592 AC: 1690 AN: 28554

American (AMR) AF: 0.518 AC: 22957 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 6924 AN: 24652

East Asian (EAS) AF: 0.206 AC: 7935 AN: 38516

South Asian (SAS) AF: 0.275 AC: 22436 AN: 81470

European-Finnish (FIN) AF: 0.491 AC: 26151 AN: 53244

Middle Eastern (MID) AF: 0.219 AC: 1144 AN: 5228

European-Non Finnish (NFE) AF: 0.383 AC: 348156 AN: 908600

Other (OTH) AF: 0.337 AC: 17812 AN: 52802

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

African (AFR) AF: 0.0705 AC: 2926 AN: 41498

American (AMR) AF: 0.432 AC: 6591 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 910 AN: 3466

East Asian (EAS) AF: 0.182 AC: 943 AN: 5172

South Asian (SAS) AF: 0.259 AC: 1246 AN: 4804

European-Finnish (FIN) AF: 0.495 AC: 5217 AN: 10532

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25180 AN: 67954

Other (OTH) AF: 0.281 AC: 593 AN: 2112

Alfa AF: 0.334 Hom.: 20601

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

- -

Nov 12, 2018

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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