rs17508082

chr10-94132372-T-Achr10-94132372-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016341.4(PLCE1):c.1405T>A(p.Ser469Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,938 control chromosomes in the GnomAD database, including 1,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (95 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1081 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.50

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PLCE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.004341513).
• BP6: Variant 10-94132372-T-A is Benign according to our data. Variant chr10-94132372-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 260711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94132372-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0294 (4478/152156) while in subpopulation NFE AF= 0.0427 (2906/67990). AF 95% confidence interval is 0.0414. There are 95 homozygotes in gnomad4. There are 2085 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4	c.1405T>A	p.Ser469Thr	missense_variant	3/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.1405T>A	p.Ser469Thr	missense_variant	3/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4478 AN: 152038 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0311 AC: 7757 AN: 249366 Hom.: 162 AF XY: 0.0320 AC XY: 4333 AN XY: 135262

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0359 AC: 52431 AN: 1461782 Hom.: 1081 Cov.: 32 AF XY: 0.0356 AC XY: 25885 AN XY: 727196

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0303

Gnomad4 ASJ exome AF: 0.0482

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0317

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0294 AC: 4478 AN: 152156 Hom.: 95 Cov.: 32 AF XY: 0.0280 AC XY: 2085 AN XY: 74416

Gnomad4 AFR AF: 0.00715

Gnomad4 AMR AF: 0.0407

Gnomad4 ASJ AF: 0.0530

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.0289

Gnomad4 NFE AF: 0.0427

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0387 Hom.: 40

Bravo AF: 0.0305

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.00555 AC: 23

ESP6500EA AF: 0.0424 AC: 356

ExAC AF: 0.0312 AC: 3778

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0488

EpiControl AF: 0.0530

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2021	- -

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. -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.084	T;.;.
Eigen	Benign	0.020
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T;T;.
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	0.87	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.68	P;P;P
Vest4		0.13
MPC		0.17
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.46

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: rs17508082; hg19: chr10-95892129;