chr10-94030760-G-A

Variant names:

• chr10-94030760-G-A
• rs17506379
• NM_016341.4:c.-287G>A

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.-287G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 428,654 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (1 hom.)
• Consequence: PLCE1 NM_016341.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.50
• Publications: 1 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 (BayesDel_noAF=-0.82).
• BP6: Variant 10-94030760-G-A is Benign according to our data. Variant chr10-94030760-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 301672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00401 (610/152132) while in subpopulation NFE AF = 0.00722 (491/67988). AF 95% confidence interval is 0.00669. There are 3 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.-287G>A		5_prime_UTR_variant	Exon 2 of 33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.-287G>A		5_prime_UTR_variant	Exon 2 of 33	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152014 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00722

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00499 AC: 1381 AN: 276522 Hom.: 1 AF XY: 0.00445 AC XY: 661 AN XY: 148528

African (AFR) AF: 0.00120 AC: 10 AN: 8364

American (AMR) AF: 0.00304 AC: 32 AN: 10534

Ashkenazi Jewish (ASJ) AF: 0.000243 AC: 2 AN: 8228

East Asian (EAS) AF: 0.00 AC: 0 AN: 15616

South Asian (SAS) AF: 0.00231 AC: 86 AN: 37166

European-Finnish (FIN) AF: 0.00268 AC: 35 AN: 13050

Middle Eastern (MID) AF: 0.000850 AC: 1 AN: 1176

European-Non Finnish (NFE) AF: 0.00690 AC: 1152 AN: 166856

Other (OTH) AF: 0.00406 AC: 63 AN: 15532

GnomAD4 genome AF: 0.00401 AC: 610 AN: 152132 Hom.: 3 Cov.: 32 AF XY: 0.00354 AC XY: 263 AN XY: 74382

African (AFR) AF: 0.00120 AC: 50 AN: 41524

American (AMR) AF: 0.00223 AC: 34 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4814

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00722 AC: 491 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00593 Hom.: 0

Bravo AF: 0.00405

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.12
DANN	Benign	0.49
PhyloP100		-2.5
PromoterAI		-0.016	Neutral
Mutation Taster		=298/2	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: rs17506379; hg19: chr10-95790517;