10-94030993-G-T

Variant names:

• chr10-94030993-G-T
• rs41291122
• NM_016341.4:c.-54G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_016341.4(PLCE1):​c.-54G>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00196 in 1,587,328 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: PLCE1 NM_016341.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00234 (357/152252) while in subpopulation NFE AF = 0.00215 (146/68008). AF 95% confidence interval is 0.00186. There are 9 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.-54G>T		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.-54G>T		5_prime_UTR_variant	Exon 2 of 33	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152134 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00192 AC: 2754 AN: 1435076 Hom.: 9 Cov.: 28 AF XY: 0.00196 AC XY: 1401 AN XY: 715604

African (AFR) AF: 0.000243 AC: 8 AN: 32886

American (AMR) AF: 0.000381 AC: 17 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00157 AC: 134 AN: 85556

European-Finnish (FIN) AF: 0.00545 AC: 290 AN: 53252

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5548

European-Non Finnish (NFE) AF: 0.00202 AC: 2199 AN: 1088312

Other (OTH) AF: 0.00173 AC: 103 AN: 59416

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152252 Hom.: 9 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74456

African (AFR) AF: 0.000265 AC: 11 AN: 41558

American (AMR) AF: 0.000393 AC: 6 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000742 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 3 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.68
PhyloP100		3.7
PromoterAI		0.0012	Neutral
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41291122; hg19: chr10-95790750;