rs41291134

chr10-94265940-G-Achr10-94265940-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016341.4(PLCE1):c.4263G>A(p.Ser1421=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,613,768 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (326 hom., cov: 32)
  • Exomes 𝑓: 0.027 (797 hom.)
• Consequence: PLCE1 NM_016341.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.352

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-94265940-G-A is Benign according to our data. Variant chr10-94265940-G-A is described in ClinVar as [Benign]. Clinvar id is 260719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94265940-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.352 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4	c.4263G>A	p.Ser1421=	synonymous_variant	16/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.4263G>A	p.Ser1421=	synonymous_variant	16/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7786 AN: 151976 Hom.: 324 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0485

Gnomad FIN AF: 0.00795

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0623

GnomAD3 exomes AF: 0.0324 AC: 8069 AN: 249280 Hom.: 212 AF XY: 0.0326 AC XY: 4403 AN XY: 135238

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.0422

Gnomad SAS exome AF: 0.0500

Gnomad FIN exome AF: 0.00942

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0265 AC: 38770 AN: 1461674 Hom.: 797 Cov.: 33 AF XY: 0.0271 AC XY: 19701 AN XY: 727144

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0360

Gnomad4 SAS exome AF: 0.0506

Gnomad4 FIN exome AF: 0.00844

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0513 AC: 7800 AN: 152094 Hom.: 326 Cov.: 32 AF XY: 0.0506 AC XY: 3765 AN XY: 74354

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0393

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0363

Gnomad4 SAS AF: 0.0486

Gnomad4 FIN AF: 0.00795

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0607

Alfa AF: 0.0344 Hom.: 106

Bravo AF: 0.0564

Asia WGS AF: 0.0500 AC: 175 AN: 3476

EpiCase AF: 0.0244

EpiControl AF: 0.0273

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nephrotic syndrome, type 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.3
Dann	Benign	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

Other links and lift over

dbSNP: rs41291134; hg19: chr10-96025697; COSMIC: COSV53364412;