NM_001144967.3:c.2690G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM2PP3_ModeratePP5_Very_Strong

The NM_001144967.3(NEDD4L):c.2690G>A(p.Arg897Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEDD4L
NM_001144967.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 10.0

Variant links:

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]

NEDD4L links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1

Transcript NM_001144967.3 (NEDD4L) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

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 [Pathogenic]. Clinvar id is 225190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.2690G>A	p.Arg897Gln	missense_variant	Exon 29 of 31	ENST00000400345.8	NP_001138439.1	Q96PU5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8 link	c.2690G>A	p.Arg897Gln	missense_variant	Exon 29 of 31	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as c.2690G>A (p.Arg897Gln). 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 225190). 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. Experimental studies have shown that this missense change affects NEDD4L function (PMID: 27694961). For these reasons, this variant has been classified as Pathogenic. -

May 14, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 16, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 26, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Periventricular nodular heterotopia with syndactyly, cleft palate and developmental delay

Pathogenic:1

Apr 02, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Intellectual disability

Uncertain:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

.;T;.;.;.;.;.;.;.;.;.;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;.;D;D;D;.;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.4

.;M;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.82

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over