chr10-94265734-A-C

Variant names:

• chr10-94265734-A-C
• rs3740360
• NM_016341.4:c.4115+26A>C

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.4115+26A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,394 control chromosomes in the GnomAD database, including 10,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (715 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9286 hom.)
• Consequence: PLCE1 NM_016341.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.22
• Publications: 20 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=-0.9).
• BP6: Variant 10-94265734-A-C is Benign according to our data. Variant chr10-94265734-A-C is described in ClinVar as Benign. ClinVar VariationId is 1296591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.4115+26A>C		intron_variant	Intron 15 of 32	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.4115+26A>C		intron_variant	Intron 15 of 32	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13120 AN: 152094 Hom.: 716 Cov.: 31

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0956

GnomAD2 exomes AF: 0.0974 AC: 24269 AN: 249096 AF XY: 0.0985

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0650

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.107 AC: 156353 AN: 1461182 Hom.: 9286 Cov.: 33 AF XY: 0.107 AC XY: 77440 AN XY: 726920

African (AFR) AF: 0.0237 AC: 794 AN: 33476

American (AMR) AF: 0.0686 AC: 3067 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4847 AN: 26132

East Asian (EAS) AF: 0.198 AC: 7870 AN: 39672

South Asian (SAS) AF: 0.0411 AC: 3542 AN: 86254

European-Finnish (FIN) AF: 0.0705 AC: 3765 AN: 53410

Middle Eastern (MID) AF: 0.154 AC: 891 AN: 5768

European-Non Finnish (NFE) AF: 0.112 AC: 124928 AN: 1111382

Other (OTH) AF: 0.110 AC: 6649 AN: 60364

GnomAD4 genome AF: 0.0862 AC: 13119 AN: 152212 Hom.: 715 Cov.: 31 AF XY: 0.0839 AC XY: 6244 AN XY: 74406

African (AFR) AF: 0.0233 AC: 968 AN: 41536

American (AMR) AF: 0.0875 AC: 1336 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 681 AN: 3472

East Asian (EAS) AF: 0.189 AC: 980 AN: 5178

South Asian (SAS) AF: 0.0447 AC: 215 AN: 4812

European-Finnish (FIN) AF: 0.0730 AC: 774 AN: 10608

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7885 AN: 68010

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.104 Hom.: 826

Bravo AF: 0.0861

Asia WGS AF: 0.120 AC: 418 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.55
DANN	Benign	0.49
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs3740360; hg19: chr10-96025491; COSMIC: COSV53342707;