rs771798085

Variant names:

• chr10-94325021-AAGG-A
• rs771798085
• NM_016341.4:c.6856_6858delGAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_016341.4(PLCE1):​c.6856_6858delGAG​(p.Glu2286del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00017 in 1,614,162 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PLCE1 NM_016341.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.48
• Publications: 0 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]

NOC3L (HGNC:24034): (NOC3 like DNA replication regulator) Enables RNA binding activity. Predicted to be involved in DNA replication initiation. Predicted to act upstream of or within fat cell differentiation. Located in mitochondrion; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016341.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-94325021-AAGG-A is Benign according to our data. Variant chr10-94325021-AAGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448044.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000788 (12/152306) while in subpopulation SAS AF = 0.00249 (12/4826). AF 95% confidence interval is 0.00143. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.6856_6858delGAG	p.Glu2286del	conservative_inframe_deletion	Exon 32 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.6808_6810delGAG	p.Glu2270del	conservative_inframe_deletion	Exon 32 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.5932_5934delGAG	p.Glu1978del	conservative_inframe_deletion	Exon 31 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.6856_6858delGAG	p.Glu2286del	conservative_inframe_deletion	Exon 32 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.5932_5934delGAG	p.Glu1978del	conservative_inframe_deletion	Exon 31 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.6856_6858delGAG	p.Glu2286del	conservative_inframe_deletion	Exon 33 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000393 AC: 98 AN: 249516 AF XY: 0.000532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000179 AC: 262 AN: 1461856 Hom.: 2 AF XY: 0.000250 AC XY: 182 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00282 AC: 243 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111984

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=81/19	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs771798085;

hg19: chr10-96084778;