rs3203713

Positions:

• chr10-94327971-A-G
• chr10-94327971-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016341.4(PLCE1):​c.*28A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 531,220 control chromosomes in the GnomAD database, including 6,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1594 hom., cov: 33)
  • Exomes 𝑓: 0.15 (4829 hom.)
• Consequence: PLCE1 NM_016341.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.11

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]

NOC3L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 10-94327971-A-G is Benign according to our data. Variant chr10-94327971-A-G is described in ClinVar as [Benign]. Clinvar id is 301735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94327971-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4	c.*28A>G		3_prime_UTR_variant	33/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.*28A>G		3_prime_UTR_variant	33/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20962 AN: 152068 Hom.: 1594 Cov.: 33

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.135 AC: 32566 AN: 241530 Hom.: 2623 AF XY: 0.141 AC XY: 18619 AN XY: 132392

Gnomad AFR exome AF: 0.0956

Gnomad AMR exome AF: 0.0750

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.00169

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.149 AC: 56548 AN: 379034 Hom.: 4829 Cov.: 0 AF XY: 0.154 AC XY: 33248 AN XY: 215846

Gnomad4 AFR exome AF: 0.0981

Gnomad4 AMR exome AF: 0.0765

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.00175

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.138 AC: 20958 AN: 152186 Hom.: 1594 Cov.: 33 AF XY: 0.137 AC XY: 10227 AN XY: 74408

Gnomad4 AFR AF: 0.0980

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.155

Alfa AF: 0.160 Hom.: 1207

Bravo AF: 0.129

Asia WGS AF: 0.0890 AC: 309 AN: 3478

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.98

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: rs3203713; hg19: chr10-96087728;