chr10-94032247-T-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_016341.4(PLCE1):​c.1201T>C​(p.Tyr401His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,210 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y401C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.04

Publications

0 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013280332).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000328 (50/152212) while in subpopulation AFR AF = 0.00106 (44/41540). AF 95% confidence interval is 0.00081. There are 1 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCE1NM_016341.4 linkc.1201T>C p.Tyr401His missense_variant Exon 2 of 33 ENST00000371380.8 NP_057425.3 Q9P212-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLCE1ENST00000371380.8 linkc.1201T>C p.Tyr401His missense_variant Exon 2 of 33 1 NM_016341.4 ENSP00000360431.2 Q9P212-1

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152094
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00106
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000727
AC:
18
AN:
247446
AF XY:
0.0000447
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1460998
Hom.:
1
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
726786
show subpopulations
African (AFR)
AF:
0.00111
AC:
37
AN:
33436
American (AMR)
AF:
0.0000224
AC:
1
AN:
44660
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26116
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86204
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53262
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111532
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60352
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152212
Hom.:
1
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74432
show subpopulations
African (AFR)
AF:
0.00106
AC:
44
AN:
41540
American (AMR)
AF:
0.000196
AC:
3
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
67990
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.000382
ESP6500AA
AF:
0.000796
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000993
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephrotic syndrome, type 3 Uncertain:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Apr 11, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:2
Jun 19, 2018
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 29, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 401 of the PLCE1 protein (p.Tyr401His). This variant is present in population databases (rs201401363, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PLCE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 586318). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.064
T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.0046
T
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L
PhyloP100
1.0
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.34
N
REVEL
Benign
0.064
Sift
Benign
0.37
T
Sift4G
Benign
0.48
T
Polyphen
0.0
B
Vest4
0.14
MVP
0.51
MPC
0.11
ClinPred
0.024
T
GERP RS
4.5
Varity_R
0.071
gMVP
0.46
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs201401363; hg19: chr10-95792004; API