10-94279849-A-G

Position:

• chr10-94279849-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016341.4(PLCE1):​c.4733A>G​(p.Asn1578Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,718 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (16 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.102

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCE1. . Gene score misZ 1.381 (greater than the threshold 3.09). Trascript score misZ 3.1046 (greater than threshold 3.09). GenCC has associacion of gene with nephrotic syndrome, type 3, familial idiopathic steroid-resistant nephrotic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002470851).
• BP6: Variant 10-94279849-A-G is Benign according to our data. Variant chr10-94279849-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 768379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94279849-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00687 (1047/152316) while in subpopulation AFR AF= 0.0234 (971/41570). AF 95% confidence interval is 0.0221. There are 9 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.4733A>G	p.Asn1578Ser	missense_variant	20/33	ENST00000371380.8	NP_057425.3
PLCE1-AS1	NR_033969.1	n.849T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.4733A>G	p.Asn1578Ser	missense_variant	20/33	1	NM_016341.4	ENSP00000360431	P1
PLCE1-AS1	ENST00000425267.8	n.826T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1043 AN: 152198 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00180 AC: 448 AN: 249066 Hom.: 7 AF XY: 0.00121 AC XY: 163 AN XY: 135096

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000821 AC: 1200 AN: 1461402 Hom.: 16 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 727040

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000963

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00687 AC: 1047 AN: 152316 Hom.: 9 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74478

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00102 Hom.: 3

Bravo AF: 0.00769

ESP6500AA AF: 0.0227 AC: 86

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.00206 AC: 249

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

Nephrotic syndrome, type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.4
DANN	Benign	0.79
DEOGEN2	Benign	0.057	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.74	T;T;.
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.25	N;N;N
REVEL	Benign	0.017
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.010	B;B;B
Vest4		0.053
MVP		0.33
MPC		0.37
ClinPred		0.00089	T
GERP RS		-2.7
Varity_R		0.026
gMVP		0.11

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: rs61732525; hg19: chr10-96039606;