rs17508082

Variant names:

• chr10-94132372-T-A
• rs17508082
• NM_016341.4:c.1405T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-94132372-T-A
• chr10-94132372-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016341.4(PLCE1):​c.1405T>A​(p.Ser469Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,938 control chromosomes in the GnomAD database, including 1,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (95 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1081 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.50
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004341513).
• BP6: Variant 10-94132372-T-A is Benign according to our data. Variant chr10-94132372-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0294 (4478/152156) while in subpopulation NFE AF = 0.0427 (2906/67990). AF 95% confidence interval is 0.0414. There are 95 homozygotes in GnomAd4. There are 2085 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 95 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.1405T>A	p.Ser469Thr	missense	Exon 3 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.1405T>A	p.Ser469Thr	missense	Exon 3 of 33	NP_001275918.1
	PLCE1	NM_001165979.2		c.481T>A	p.Ser161Thr	missense	Exon 2 of 32	NP_001159451.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.1405T>A	p.Ser469Thr	missense	Exon 3 of 33	ENSP00000360431.2
	PLCE1	ENST00000371375.2	TSL:1	c.481T>A	p.Ser161Thr	missense	Exon 2 of 31	ENSP00000360426.1
	PLCE1	ENST00000875452.1		c.1405T>A	p.Ser469Thr	missense	Exon 4 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4478 AN: 152038 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0311 AC: 7757 AN: 249366 AF XY: 0.0320

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0359 AC: 52431 AN: 1461782 Hom.: 1081 Cov.: 32 AF XY: 0.0356 AC XY: 25885 AN XY: 727196

African (AFR) AF: 0.00618 AC: 207 AN: 33480

American (AMR) AF: 0.0303 AC: 1353 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0482 AC: 1259 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0114 AC: 987 AN: 86258

European-Finnish (FIN) AF: 0.0317 AC: 1692 AN: 53410

Middle Eastern (MID) AF: 0.0468 AC: 270 AN: 5768

European-Non Finnish (NFE) AF: 0.0400 AC: 44485 AN: 1111916

Other (OTH) AF: 0.0360 AC: 2175 AN: 60392

GnomAD4 genome AF: 0.0294 AC: 4478 AN: 152156 Hom.: 95 Cov.: 32 AF XY: 0.0280 AC XY: 2085 AN XY: 74416

African (AFR) AF: 0.00715 AC: 297 AN: 41532

American (AMR) AF: 0.0407 AC: 622 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4818

European-Finnish (FIN) AF: 0.0289 AC: 306 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0427 AC: 2906 AN: 67990

Other (OTH) AF: 0.0403 AC: 85 AN: 2110

Alfa AF: 0.0387 Hom.: 40

Bravo AF: 0.0305

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.00555 AC: 23

ESP6500EA AF: 0.0424 AC: 356

ExAC AF: 0.0312 AC: 3778

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0488

EpiControl AF: 0.0530

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.020
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.031	D
Polyphen		0.68	P
Vest4		0.13
MPC		0.17
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.46
Mutation Taster		=99/1	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: rs17508082; hg19: chr10-95892129;