10-94298541-C-T

Variant names:

• chr10-94298541-C-T
• rs3765524
• NM_016341.4:c.5330C>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.5330C>T​(p.Thr1777Ile) variant causes a missense change. The variant allele was found at a frequency of 0.277 in 1,613,514 control chromosomes in the GnomAD database, including 64,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1777A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7705 hom., cov: 31)
  • Exomes 𝑓: 0.27 (56343 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.13
• Publications: 116 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=7.8240037E-4).
• BP6: Variant 10-94298541-C-T is Benign according to our data. Variant chr10-94298541-C-T is described in ClinVar as Benign. ClinVar VariationId is 260724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 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.5330C>T	p.Thr1777Ile	missense	Exon 24 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.5282C>T	p.Thr1761Ile	missense	Exon 24 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.4406C>T	p.Thr1469Ile	missense	Exon 23 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.5330C>T	p.Thr1777Ile	missense	Exon 24 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.4406C>T	p.Thr1469Ile	missense	Exon 23 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.5330C>T	p.Thr1777Ile	missense	Exon 25 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47289 AN: 151664 Hom.: 7685 Cov.: 31

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.267 AC: 66545 AN: 249386 AF XY: 0.271

Gnomad AFR exome AF: 0.421

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.273 AC: 398957 AN: 1461732 Hom.: 56343 Cov.: 36 AF XY: 0.275 AC XY: 200008 AN XY: 727180

African (AFR) AF: 0.426 AC: 14269 AN: 33476

American (AMR) AF: 0.174 AC: 7787 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11039 AN: 26136

East Asian (EAS) AF: 0.235 AC: 9313 AN: 39696

South Asian (SAS) AF: 0.263 AC: 22665 AN: 86256

European-Finnish (FIN) AF: 0.206 AC: 11015 AN: 53420

Middle Eastern (MID) AF: 0.435 AC: 2506 AN: 5766

European-Non Finnish (NFE) AF: 0.272 AC: 302416 AN: 1111866

Other (OTH) AF: 0.297 AC: 17947 AN: 60392

GnomAD4 genome AF: 0.312 AC: 47341 AN: 151782 Hom.: 7705 Cov.: 31 AF XY: 0.305 AC XY: 22649 AN XY: 74160

African (AFR) AF: 0.413 AC: 17052 AN: 41326

American (AMR) AF: 0.250 AC: 3816 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1527 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5166

South Asian (SAS) AF: 0.259 AC: 1243 AN: 4806

European-Finnish (FIN) AF: 0.192 AC: 2023 AN: 10532

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19392 AN: 67922

Other (OTH) AF: 0.330 AC: 698 AN: 2112

Alfa AF: 0.294 Hom.: 24593

Bravo AF: 0.318

TwinsUK AF: 0.276 AC: 1024

ALSPAC AF: 0.257 AC: 991

ESP6500AA AF: 0.394 AC: 1593

ESP6500EA AF: 0.286 AC: 2378

ExAC AF: 0.271 AC: 32743

Asia WGS AF: 0.283 AC: 983 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.306

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Nephrotic syndrome, type 3 (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.033
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.29
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
PhyloP100		5.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	3.8	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.079
MPC		0.50
ClinPred		0.0052	T
GERP RS		5.6
Varity_R		0.069
gMVP		0.37
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3765524; hg19: chr10-96058298; COSMIC: COSV53339317;