10-94283975-A-G

Variant names:

• chr10-94283975-A-G
• rs7084339
• NM_016341.4:c.4917+64A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016341.4(PLCE1):​c.4917+64A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,572,808 control chromosomes in the GnomAD database, including 75,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8702 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66648 hom.)
• Consequence: PLCE1 NM_016341.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.783

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-AS1 (HGNC:45193): (PLCE1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-94283975-A-G is Benign according to our data. Variant chr10-94283975-A-G is described in ClinVar as [Benign]. Clinvar id is 1235235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.4917+64A>G		intron_variant	Intron 21 of 32	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.4917+64A>G		intron_variant	Intron 21 of 32	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50539 AN: 151986 Hom.: 8682 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.344

GnomAD4 exome AF: 0.302 AC: 429660 AN: 1420704 Hom.: 66648 AF XY: 0.304 AC XY: 214929 AN XY: 707490

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.333 AC: 50592 AN: 152104 Hom.: 8702 Cov.: 32 AF XY: 0.325 AC XY: 24182 AN XY: 74370

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.343

Alfa AF: 0.269 Hom.: 1159

Bravo AF: 0.338

Asia WGS AF: 0.287 AC: 997 AN: 3478

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

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.70

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: rs7084339; hg19: chr10-96043732; COSMIC: COSV53342714;