10-94030912-G-A

Variant names:

• chr10-94030912-G-A
• rs10882386
• NM_016341.4:c.-135G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.140
• Publications: 10 publications found

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]

PLCE1 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.-135G>A		5_prime_UTR_variant	Exon 2 of 33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.-135G>A		5_prime_UTR_variant	Exon 2 of 33	1	NM_016341.4	ENSP00000360431.2

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

African (AFR) AF: 0.437 AC: 7804 AN: 17856

American (AMR) AF: 0.156 AC: 6226 AN: 39894

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 4967 AN: 20356

East Asian (EAS) AF: 0.467 AC: 16274 AN: 34816

South Asian (SAS) AF: 0.302 AC: 19788 AN: 65424

European-Finnish (FIN) AF: 0.285 AC: 13458 AN: 47212

Middle Eastern (MID) AF: 0.245 AC: 645 AN: 2638

European-Non Finnish (NFE) AF: 0.258 AC: 112182 AN: 435206

Other (OTH) AF: 0.277 AC: 9690 AN: 34920

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

African (AFR) AF: 0.444 AC: 18416 AN: 41442

American (AMR) AF: 0.222 AC: 3384 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 816 AN: 3464

East Asian (EAS) AF: 0.437 AC: 2263 AN: 5174

South Asian (SAS) AF: 0.315 AC: 1519 AN: 4824

European-Finnish (FIN) AF: 0.306 AC: 3233 AN: 10570

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17283 AN: 67960

Other (OTH) AF: 0.283 AC: 599 AN: 2116

Alfa AF: 0.270 Hom.: 7460

Bravo AF: 0.313

Asia WGS AF: 0.362 AC: 1258 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.81
CADD	Benign	3.7
DANN	Benign	0.54
PhyloP100		-0.14
PromoterAI		-0.0090	Neutral
Mutation Taster		=296/4	polymorphism (auto)

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

Other links and lift over

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