Genetic Variant NM_016341.4:c.513G>A (chr10-94031559-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_016341.4(PLCE1):c.513G>A(p.Val171Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,284 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

PLCE1
NM_016341.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -1.74

Publications

2 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: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-94031559-G-A is Benign according to our data. Variant chr10-94031559-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260723.

BP7

Synonymous conserved (PhyloP=-1.74 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00114 (174/152246) while in subpopulation AMR AF = 0.00151 (23/15280). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.513G>A	p.Val171Val	synonymous	Exon 2 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.513G>A	p.Val171Val	synonymous	Exon 2 of 33	NP_001275918.1	B7ZM61

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.513G>A	p.Val171Val	synonymous	Exon 2 of 33	ENSP00000360431.2	Q9P212-1
PLCE1	ENST00000875452.1		c.513G>A	p.Val171Val	synonymous	Exon 3 of 34	ENSP00000545511.1
PLCE1	ENST00000875451.1		c.513G>A	p.Val171Val	synonymous	Exon 2 of 33	ENSP00000545510.1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00140

AC:

345

AN:

246978

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00946

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000496

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.00283

GnomAD4 exome

AF:

0.00110

AC:

1608

AN:

1460038

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

878

AN XY:

726432

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33456

American (AMR)

AF:

0.00110

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

266

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00140

AC:

121

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51898

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000826

AC:

918

AN:

1111786

Other (OTH)

AF:

0.00247

AC:

149

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00114

AC:

174

AN:

152246

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41554

American (AMR)

AF:

0.00151

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00145

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

68016

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00166

Hom.:

Bravo

AF:

0.00117

EpiCase

AF:

0.00202

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Focal segmental glomerulosclerosis (1)

Nephrotic syndrome, type 3 (1)

PLCE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.021

(source)

DANN

Benign

0.42

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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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