NM_016341.4:c.4059C>G

Variant names:

• chr10-94265652-C-G
• rs61751499
• NM_016341.4:c.4059C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_016341.4(PLCE1):​c.4059C>G​(p.Phe1353Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1353F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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.4059C>G	p.Phe1353Leu	missense	Exon 15 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.4011C>G	p.Phe1337Leu	missense	Exon 15 of 33	NP_001275918.1
	PLCE1	NM_001165979.2		c.3135C>G	p.Phe1045Leu	missense	Exon 14 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.4059C>G	p.Phe1353Leu	missense	Exon 15 of 33	ENSP00000360431.2
	PLCE1	ENST00000371375.2	TSL:1	c.3135C>G	p.Phe1045Leu	missense	Exon 14 of 31	ENSP00000360426.1
	PLCE1	ENST00000692396.1		c.4011C>G	p.Phe1337Leu	missense	Exon 15 of 33	ENSP00000508605.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461248 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111506

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00343940), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 6

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	4.0
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.41
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.29
Sift	Uncertain	0.019	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.62		Loss of methylation at K1352 (P = 0.0841)
MVP		0.40
MPC		1.5
ClinPred		0.99	D
GERP RS		-8.6
Varity_R		0.27
gMVP		0.68
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61751499; hg19: chr10-96025409;