rs61732522

Positions:

• chr10-94252351-C-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.3132C>T​(p.His1044=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,614,042 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (126 hom.)
• Consequence: PLCE1 NM_016341.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.87

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=-0.75).
• BP6: Variant 10-94252351-C-T is Benign according to our data. Variant chr10-94252351-C-T is described in ClinVar as [Benign]. Clinvar id is 260717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94252351-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.3132C>T	p.His1044=	synonymous_variant	9/33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.3132C>T	p.His1044=	synonymous_variant	9/33	1	NM_016341.4	ENSP00000360431	P1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3616 AN: 152108 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.00944 AC: 2354 AN: 249322 Hom.: 52 AF XY: 0.00867 AC XY: 1172 AN XY: 135254

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.00947

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00578 AC: 8456 AN: 1461816 Hom.: 126 Cov.: 31 AF XY: 0.00571 AC XY: 4155 AN XY: 727208

Gnomad4 AFR exome AF: 0.0699

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00914

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00545

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00354

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0238 AC: 3626 AN: 152226 Hom.: 97 Cov.: 32 AF XY: 0.0236 AC XY: 1756 AN XY: 74462

Gnomad4 AFR AF: 0.0675

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0128 Hom.: 31

Bravo AF: 0.0270

Asia WGS AF: 0.0130 AC: 46 AN: 3476

EpiCase AF: 0.00758

EpiControl AF: 0.00777

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nephrotic syndrome, type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.9
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61732522; hg19: chr10-96012108;