10-94284854-G-A

Position:

• chr10-94284854-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_016341.4(PLCE1):​c.4924G>A​(p.Asp1642Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCE1. . Gene score misZ 1.381 (greater than the threshold 3.09). Trascript score misZ 3.1046 (greater than threshold 3.09). GenCC has associacion of gene with nephrotic syndrome, type 3, familial idiopathic steroid-resistant nephrotic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.4924G>A	p.Asp1642Asn	missense_variant	22/33	ENST00000371380.8	NP_057425.3
PLCE1-AS1	NR_033969.1	n.231-1368C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.4924G>A	p.Asp1642Asn	missense_variant	22/33	1	NM_016341.4	ENSP00000360431	P1
PLCE1-AS1	ENST00000425267.8	n.208-1368C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414820 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 706892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.35		Loss of ubiquitination at K1637 (P = 0.0527);.;.;
MVP		0.85
MPC		1.3
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.44
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs886047504; hg19: chr10-96044611;