NM_016341.4:c.5780A>G

Variant names:

• chr10-94306584-A-G
• rs2274223
• NM_016341.4:c.5780A>G

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.5780A>G​(p.His1927Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,668 control chromosomes in the GnomAD database, including 74,193 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. H1927L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7401 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66792 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.06
• Publications: 207 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=0.004501492).
• BP6: Variant 10-94306584-A-G is Benign according to our data. Variant chr10-94306584-A-G is described in ClinVar as Benign. ClinVar VariationId is 260728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.5780A>G	p.His1927Arg	missense	Exon 26 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.5732A>G	p.His1911Arg	missense	Exon 26 of 33	NP_001275918.1
	PLCE1	NM_001165979.2		c.4856A>G	p.His1619Arg	missense	Exon 25 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.5780A>G	p.His1927Arg	missense	Exon 26 of 33	ENSP00000360431.2
	PLCE1	ENST00000371375.2	TSL:1	c.4856A>G	p.His1619Arg	missense	Exon 25 of 31	ENSP00000360426.1
	PLCE1	ENST00000875452.1		c.5780A>G	p.His1927Arg	missense	Exon 27 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47158 AN: 151938 Hom.: 7385 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.282 AC: 70230 AN: 249328 AF XY: 0.287

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.299 AC: 436911 AN: 1461612 Hom.: 66792 Cov.: 36 AF XY: 0.301 AC XY: 218919 AN XY: 727118

African (AFR) AF: 0.354 AC: 11842 AN: 33472

American (AMR) AF: 0.179 AC: 8023 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11339 AN: 26128

East Asian (EAS) AF: 0.236 AC: 9379 AN: 39698

South Asian (SAS) AF: 0.283 AC: 24368 AN: 86258

European-Finnish (FIN) AF: 0.226 AC: 12065 AN: 53416

Middle Eastern (MID) AF: 0.434 AC: 2506 AN: 5768

European-Non Finnish (NFE) AF: 0.304 AC: 338371 AN: 1111758

Other (OTH) AF: 0.315 AC: 19018 AN: 60392

GnomAD4 genome AF: 0.310 AC: 47199 AN: 152056 Hom.: 7401 Cov.: 32 AF XY: 0.304 AC XY: 22575 AN XY: 74316

African (AFR) AF: 0.346 AC: 14362 AN: 41456

American (AMR) AF: 0.252 AC: 3858 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1560 AN: 3468

East Asian (EAS) AF: 0.229 AC: 1178 AN: 5152

South Asian (SAS) AF: 0.281 AC: 1356 AN: 4820

European-Finnish (FIN) AF: 0.210 AC: 2222 AN: 10574

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21518 AN: 67986

Other (OTH) AF: 0.328 AC: 693 AN: 2110

Alfa AF: 0.319 Hom.: 36114

Bravo AF: 0.313

TwinsUK AF: 0.309 AC: 1147

ALSPAC AF: 0.293 AC: 1130

ESP6500AA AF: 0.334 AC: 1345

ESP6500EA AF: 0.311 AC: 2596

ExAC AF: 0.284 AC: 34369

Asia WGS AF: 0.289 AC: 1003 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.332

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.43
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.95	N
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.57
ClinPred		0.0027	T
GERP RS		5.4
Varity_R		0.068
gMVP		0.15
Mutation Taster		=100/0	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: rs2274223; hg19: chr10-96066341; COSMIC: COSV53339364;