rs139061122

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_016341.4(PLCE1):​c.-246A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 514,502 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 3 hom. )

Consequence

PLCE1
NM_016341.4 5_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.738

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: Benign. The variant received -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
Variant 10-94030801-A-G is Benign according to our data. Variant chr10-94030801-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 877653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00376 (573/152266) while in subpopulation AFR AF = 0.013 (539/41562). AF 95% confidence interval is 0.0121. There are 2 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCE1NM_016341.4 linkc.-246A>G 5_prime_UTR_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.-246A>G 5_prime_UTR_variant Exon 2 of 33 1 NM_016341.4 ENSP00000360431.2 Q9P212-1

Frequencies

GnomAD3 genomes
AF:
0.00374
AC:
569
AN:
152148
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0129
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00334
GnomAD4 exome
AF:
0.000536
AC:
194
AN:
362236
Hom.:
3
Cov.:
3
AF XY:
0.000473
AC XY:
91
AN XY:
192350
show subpopulations
African (AFR)
AF:
0.0118
AC:
125
AN:
10634
American (AMR)
AF:
0.00111
AC:
15
AN:
13490
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
11212
East Asian (EAS)
AF:
0.00
AC:
0
AN:
23806
South Asian (SAS)
AF:
0.000232
AC:
9
AN:
38862
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
20006
Middle Eastern (MID)
AF:
0.000639
AC:
1
AN:
1566
European-Non Finnish (NFE)
AF:
0.0000271
AC:
6
AN:
221546
Other (OTH)
AF:
0.00180
AC:
38
AN:
21114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
8
16
23
31
39
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00376
AC:
573
AN:
152266
Hom.:
2
Cov.:
32
AF XY:
0.00356
AC XY:
265
AN XY:
74456
show subpopulations
African (AFR)
AF:
0.0130
AC:
539
AN:
41562
American (AMR)
AF:
0.00164
AC:
25
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68010
Other (OTH)
AF:
0.00331
AC:
7
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
30
60
89
119
149
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00250
Hom.:
0
Bravo
AF:
0.00445
Asia WGS
AF:
0.00289
AC:
10
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
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 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. -

not provided Benign:1
Mar 02, 2020
GeneDx
Significance:Likely 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
-0.36
CADD
Benign
12
DANN
Benign
0.84
PhyloP100
0.74
PromoterAI
0.0030
Neutral

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs139061122; hg19: chr10-95790558; API