rs879255596

chr18-58390680-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_Moderate PP3_Moderate PP5

The NM_001144967.3(NEDD4L):c.2690G>A(p.Arg897Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 10.0

Genes affected

NEDD4L (HGNC:7728): (NEDD4 like E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript NM_001144967.3 (NEDD4L) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 18-58390680-G-A is Pathogenic according to our data. Variant chr18-58390680-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225190.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.2690G>A	p.Arg897Gln	missense_variant	29/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2690G>A	p.Arg897Gln	missense_variant	29/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445542 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717034

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2022	This missense change has been observed in individual(s) with periventricular nodular heterotopia (PMID: 27694961). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NEDD4L function (PMID: 27694961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 225190). This variant is also known as c.2690G>A (p.Arg897Gln). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 877 of the NEDD4L protein (p.Arg877Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2020	Published functional studies demonstrate a damaging effect associated with deregulation of mTORC and AKT activities and affecting neurogenesis, neuronal positioning, and terminal translocation (Broix et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Also denoted as R897Q due to alternative nomenclature; This variant is associated with the following publications: (PMID: 27694961, 28515470) -

Periventricular nodular heterotopia 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 26, 2018	- -

Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay Pathogenic:1

Pathogenic, no assertion criteria provided

research

Chelly Lab, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg University - CNRS UMR 7104 - Inserm U 964

Apr 02, 2016

- -

Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;.;D;D;D;.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;.;D;D;D;D;D;.;D;D;.;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;.;D;.;.;.;D;D;.;.;.;.
Vest4		0.82
MutPred		0.84		.;Loss of MoRF binding (P = 0.0323);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.75
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.83

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: rs879255596; hg19: chr18-56057912;