Genetic Variant PLCE1:p.His1044His (chr10-94252351-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016341.4(PLCE1):c.3132C>T(p.His1044His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,614,042 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 97 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 126 hom. )

Consequence

PLCE1
NM_016341.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.87

Publications

1 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

PLCE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-94252351-C-T is Benign according to our data. Variant chr10-94252351-C-T is described in ClinVar as Benign. ClinVar VariationId is 260717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016341.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCE1	NM_016341.4	MANE Select	c.3132C>T	p.His1044His	synonymous	Exon 9 of 33	NP_057425.3
PLCE1	NM_001288989.2		c.3132C>T	p.His1044His	synonymous	Exon 9 of 33	NP_001275918.1
PLCE1	NM_001165979.2		c.2208C>T	p.His736His	synonymous	Exon 8 of 32	NP_001159451.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.3132C>T	p.His1044His	synonymous	Exon 9 of 33	ENSP00000360431.2
PLCE1	ENST00000371375.2	TSL:1	c.2208C>T	p.His736His	synonymous	Exon 8 of 31	ENSP00000360426.1
PLCE1	ENST00000875452.1		c.3132C>T	p.His1044His	synonymous	Exon 10 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3616

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0673

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00467

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.00944

AC:

2354

AN:

249322

AF XY:

0.00867

show subpopulations

Gnomad AFR exome

AF:

0.0691

Gnomad AMR exome

AF:

0.00947

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00533

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.00578

AC:

8456

AN:

1461816

Hom.:

126

Cov.:

AF XY:

0.00571

AC XY:

4155

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0699

AC:

2340

AN:

33472

American (AMR)

AF:

0.0112

AC:

499

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00914

AC:

239

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00545

AC:

470

AN:

86256

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0387

AC:

223

AN:

5764

European-Non Finnish (NFE)

AF:

0.00354

AC:

3935

AN:

1111964

Other (OTH)

AF:

0.0120

AC:

724

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

457

915

1372

1830

2287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.0238

AC:

3626

AN:

152226

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1756

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0675

AC:

2801

AN:

41504

American (AMR)

AF:

0.0214

AC:

327

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00643

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00466

AC:

317

AN:

68018

Other (OTH)

AF:

0.0322

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0212

Hom.:

Bravo

AF:

0.0270

Asia WGS

AF:

0.0130

AC:

AN:

3476

EpiCase

AF:

0.00758

EpiControl

AF:

0.00777

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Nephrotic syndrome, type 3 (2)

Focal segmental glomerulosclerosis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.9

(source)

DANN

Benign

0.60

PhyloP100

-3.9

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over