10-93994065-A-G

Variant names:

• chr10-93994065-A-G
• rs2911857
• NM_016341.4:c.-558A>G

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.-558A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 105,918 control chromosomes in the GnomAD database, including 7,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.42 (7971 hom., cov: 26)
• Consequence: PLCE1 NM_016341.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 3 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=-0.71).
• BP6: Variant 10-93994065-A-G is Benign according to our data. Variant chr10-93994065-A-G is described in ClinVar as [Benign]. Clinvar id is 301666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.-558A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 33	ENST00000371380.8	NP_057425.3
PLCE1	NM_016341.4	c.-558A>G		5_prime_UTR_variant	Exon 1 of 33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.-558A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 33	1	NM_016341.4	ENSP00000360431.2
PLCE1	ENST00000371380.8	c.-558A>G		5_prime_UTR_variant	Exon 1 of 33	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 44514 AN: 105810 Hom.: 7957 Cov.: 26

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.319

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.371

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.421 AC: 44572 AN: 105918 Hom.: 7971 Cov.: 26 AF XY: 0.422 AC XY: 22033 AN XY: 52186

African (AFR) AF: 0.586 AC: 20137 AN: 34362

American (AMR) AF: 0.364 AC: 3709 AN: 10176

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 910 AN: 2332

East Asian (EAS) AF: 0.613 AC: 2575 AN: 4198

South Asian (SAS) AF: 0.452 AC: 1644 AN: 3638

European-Finnish (FIN) AF: 0.345 AC: 2546 AN: 7388

Middle Eastern (MID) AF: 0.313 AC: 67 AN: 214

European-Non Finnish (NFE) AF: 0.293 AC: 12140 AN: 41464

Other (OTH) AF: 0.370 AC: 564 AN: 1526

Alfa AF: 0.327 Hom.: 544

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.5
DANN	Benign	0.75
PhyloP100		-1.3
PromoterAI		0.13	Neutral
Mutation Taster		=300/0	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: rs2911857; hg19: chr10-95753822; COSMIC: COSV53373975;