10-94030912-G-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.-135G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 850,334 control chromosomes in the GnomAD database, including 35,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8116 hom., cov: 32)
  • Exomes 𝑓: 0.27 (27797 hom.)
• Consequence: PLCE1 NM_016341.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.140

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-94030912-G-A is Benign according to our data. Variant chr10-94030912-G-A is described in ClinVar as [Benign]. Clinvar id is 301676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94030912-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4	c.-135G>A		5_prime_UTR_variant	2/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.-135G>A		5_prime_UTR_variant	2/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47769 AN: 151894 Hom.: 8111 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.274 AC: 191034 AN: 698322 Hom.: 27797 Cov.: 9 AF XY: 0.275 AC XY: 102490 AN XY: 373362

Gnomad4 AFR exome AF: 0.437

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.302

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.314 AC: 47790 AN: 152012 Hom.: 8116 Cov.: 32 AF XY: 0.316 AC XY: 23485 AN XY: 74308

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.437

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.306

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.283

Alfa AF: 0.264 Hom.: 5387

Bravo AF: 0.313

Asia WGS AF: 0.362 AC: 1258 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

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	-0.81
Cadd	Benign	3.7
Dann	Benign	0.54

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: rs10882386; hg19: chr10-95790669; COSMIC: COSV53373273;