10-94171330-G-T

Variant names:

• chr10-94171330-G-T
• rs17417407
• NM_016341.4:c.1643G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016341.4(PLCE1):​c.1643G>T​(p.Arg548Leu) variant causes a missense change. The variant allele was found at a frequency of 0.175 in 1,613,912 control chromosomes in the GnomAD database, including 26,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2389 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23934 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.76
• Publications: 44 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: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017680526).
• BP6: Variant 10-94171330-G-T is Benign according to our data. Variant chr10-94171330-G-T is described in ClinVar as Benign. ClinVar VariationId is 260712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.312 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.1643G>T	p.Arg548Leu	missense	Exon 4 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.1643G>T	p.Arg548Leu	missense	Exon 4 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.719G>T	p.Arg240Leu	missense	Exon 3 of 32	NP_001159451.1	Q9P212-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.1643G>T	p.Arg548Leu	missense	Exon 4 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.719G>T	p.Arg240Leu	missense	Exon 3 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.1643G>T	p.Arg548Leu	missense	Exon 5 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26145 AN: 151978 Hom.: 2384 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.172 AC: 42951 AN: 249426 AF XY: 0.182

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0932

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.176 AC: 256581 AN: 1461814 Hom.: 23934 Cov.: 34 AF XY: 0.180 AC XY: 130640 AN XY: 727214

African (AFR) AF: 0.194 AC: 6497 AN: 33480

American (AMR) AF: 0.0976 AC: 4365 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5614 AN: 26136

East Asian (EAS) AF: 0.158 AC: 6290 AN: 39698

South Asian (SAS) AF: 0.310 AC: 26710 AN: 86256

European-Finnish (FIN) AF: 0.130 AC: 6922 AN: 53420

Middle Eastern (MID) AF: 0.214 AC: 1234 AN: 5768

European-Non Finnish (NFE) AF: 0.169 AC: 187989 AN: 1111936

Other (OTH) AF: 0.181 AC: 10960 AN: 60396

GnomAD4 genome AF: 0.172 AC: 26162 AN: 152098 Hom.: 2389 Cov.: 32 AF XY: 0.171 AC XY: 12727 AN XY: 74348

African (AFR) AF: 0.189 AC: 7847 AN: 41494

American (AMR) AF: 0.146 AC: 2231 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.129 AC: 666 AN: 5150

South Asian (SAS) AF: 0.326 AC: 1565 AN: 4802

European-Finnish (FIN) AF: 0.123 AC: 1305 AN: 10594

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11209 AN: 67994

Other (OTH) AF: 0.174 AC: 366 AN: 2108

Alfa AF: 0.166 Hom.: 7267

Bravo AF: 0.171

TwinsUK AF: 0.169 AC: 628

ALSPAC AF: 0.163 AC: 630

ESP6500AA AF: 0.174 AC: 711

ESP6500EA AF: 0.170 AC: 1427

ExAC AF: 0.178 AC: 21525

EpiCase AF: 0.178

EpiControl AF: 0.183

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Nephrotic syndrome, type 3 (3)
-	-	3	not specified (3)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.086
Sift	Benign	0.047	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.30
MPC		0.51
ClinPred		0.011	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.55
Mutation Taster		=97/3	polymorphism (auto)

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: rs17417407; hg19: chr10-95931087; COSMIC: COSV53342614;