10-94227423-G-T

Position:

chr10-94227423-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_016341.4(PLCE1):c.1927G>T(p.Ala643Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00161 in 1,614,056 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 5 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 5.46

Variant links:

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 links:

PLCE1 (HGNC:):

PLCE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.026815474).

BP6

Variant 10-94227423-G-T is Benign according to our data. Variant chr10-94227423-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448042.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr10-94227423-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (198/152286) while in subpopulation NFE AF= 0.00228 (155/68018). AF 95% confidence interval is 0.00199. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.1927G>T	p.Ala643Ser	missense_variant	5/33	ENST00000371380.8	NP_057425.3	Q9P212-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8 linkuse as main transcript	c.1927G>T	p.Ala643Ser	missense_variant	5/33	1	NM_016341.4	ENSP00000360431.2		Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00131

AC:

328

AN:

249546

Hom.:

AF XY:

0.00131

AC XY:

177

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00255

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00164

AC:

2393

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1162

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00296

Gnomad4 NFE exome

AF:

0.00182

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152286

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00228

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.00201

AC:

ExAC

AF:

0.00154

AC:

187

EpiCase

AF:

0.00147

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PLCE1 p.Ala643Ser variant was identified in the literature in 1 of 69 families with focal and segmental glomerulosclerosis (Gbadegesin_2009_PMID:18975016). The variant was identified in dbSNP (ID: rs61886330), ClinVar (classified as uncertain significance by Athena Diagnostics Inc) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 383 of 280922 chromosomes (1 homozygous) at a frequency of 0.001363 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 63 of 25038 chromosomes (freq: 0.002516), Other in 15 of 7146 chromosomes (freq: 0.002099), European (non-Finnish) in 270 of 128664 chromosomes (freq: 0.002098), South Asian in 16 of 30602 chromosomes (freq: 0.000523), Ashkenazi Jewish in 4 of 10360 chromosomes (freq: 0.000386), Latino in 13 of 35376 chromosomes (freq: 0.000368) and African in 2 of 24200 chromosomes (freq: 0.000083), but was not observed in the East Asian population. The p.Ala643 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 28, 2016

- -

Nephrotic syndrome, type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

PLCE1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.99

L;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.88

N;N;N

REVEL

Benign

0.071

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.42

B;P;P

Vest4

0.59

MVP

0.55

MPC

0.33

ClinPred

0.063

GERP RS

4.8

Varity_R

0.054

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over