chr10-94171416-G-A

Variant names:

• chr10-94171416-G-A
• rs141639885
• NM_016341.4:c.1729G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000371380.8(PLCE1):​c.1729G>A​(p.Ala577Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,614,182 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: PLCE1 ENST00000371380.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 6.74
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007831275).
• BP6: Variant 10-94171416-G-A is Benign according to our data. Variant chr10-94171416-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260713.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00418 (636/152316) while in subpopulation AFR AF = 0.0132 (549/41578). AF 95% confidence interval is 0.0123. There are 5 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371380.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.1729G>A	p.Ala577Thr	missense	Exon 4 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.1729G>A	p.Ala577Thr	missense	Exon 4 of 33	NP_001275918.1
	PLCE1	NM_001165979.2		c.805G>A	p.Ala269Thr	missense	Exon 3 of 32	NP_001159451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.1729G>A	p.Ala577Thr	missense	Exon 4 of 33	ENSP00000360431.2
	PLCE1	ENST00000371375.2	TSL:1	c.805G>A	p.Ala269Thr	missense	Exon 3 of 31	ENSP00000360426.1
	PLCE1	ENST00000692396.1		c.1729G>A	p.Ala577Thr	missense	Exon 4 of 33	ENSP00000508605.1

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 636 AN: 152198 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00115 AC: 286 AN: 249376 AF XY: 0.000835

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000407 AC: 595 AN: 1461866 Hom.: 6 Cov.: 33 AF XY: 0.000342 AC XY: 249 AN XY: 727240

African (AFR) AF: 0.0116 AC: 388 AN: 33480

American (AMR) AF: 0.00186 AC: 83 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111988

Other (OTH) AF: 0.000993 AC: 60 AN: 60394

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152316 Hom.: 5 Cov.: 32 AF XY: 0.00377 AC XY: 281 AN XY: 74470

African (AFR) AF: 0.0132 AC: 549 AN: 41578

American (AMR) AF: 0.00451 AC: 69 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00509

ESP6500AA AF: 0.0140 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Kidney disorder (1)
-	-	1	Nephrotic syndrome, type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.078
Sift	Benign	0.15	T
Sift4G	Benign	0.081	T
Polyphen		0.57	P
Vest4		0.36
MVP		0.58
MPC		0.11
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.33
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs141639885; hg19: chr10-95931173;