rs61732525

Variant names:

• chr10-94279849-A-G
• rs61732525
• NM_016341.4:c.4733A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-94279849-A-G
• chr10-94279849-A-T

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.4733A>G​(p.Asn1578Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,718 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1578I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (16 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.102
• Publications: 5 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-AS1 (HGNC:45193): (PLCE1 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002470851).
• BP6: Variant 10-94279849-A-G is Benign according to our data. Variant chr10-94279849-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 768379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00687 (1047/152316) while in subpopulation AFR AF = 0.0234 (971/41570). AF 95% confidence interval is 0.0221. There are 9 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4733A>G	p.Asn1578Ser	missense	Exon 20 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.4685A>G	p.Asn1562Ser	missense	Exon 20 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.3809A>G	p.Asn1270Ser	missense	Exon 19 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.4733A>G	p.Asn1578Ser	missense	Exon 20 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.3809A>G	p.Asn1270Ser	missense	Exon 19 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.4733A>G	p.Asn1578Ser	missense	Exon 21 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1043 AN: 152198 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00180 AC: 448 AN: 249066 AF XY: 0.00121

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000821 AC: 1200 AN: 1461402 Hom.: 16 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 727040

African (AFR) AF: 0.0240 AC: 802 AN: 33450

American (AMR) AF: 0.00217 AC: 97 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5760

European-Non Finnish (NFE) AF: 0.0000963 AC: 107 AN: 1111660

Other (OTH) AF: 0.00237 AC: 143 AN: 60364

GnomAD4 genome AF: 0.00687 AC: 1047 AN: 152316 Hom.: 9 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74478

African (AFR) AF: 0.0234 AC: 971 AN: 41570

American (AMR) AF: 0.00320 AC: 49 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00243 Hom.: 7

Bravo AF: 0.00769

ESP6500AA AF: 0.0227 AC: 86

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.00206 AC: 249

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Kidney disorder (1)
-	-	1	Nephrotic syndrome, type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.4
DANN	Benign	0.79
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.10
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.017
Sift	Benign	0.57	T
Sift4G	Benign	0.57	T
Polyphen		0.010	B
Vest4		0.053
MVP		0.33
MPC		0.37
ClinPred		0.00089	T
GERP RS		-2.7
Varity_R		0.026
gMVP		0.11
Mutation Taster		=100/0	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: rs61732525; hg19: chr10-96039606;