rs879255597

Positions:

chr18-58390667-G-A

Variant summary

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

The ENST00000400345.8(NEDD4L):c.2677G>A(p.Glu893Lys) 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 Likely pathogenic (★★). 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
ENST00000400345.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.96

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1

Transcript ENST00000400345.8 (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, 0.883

PP5

Variant 18-58390667-G-A is Pathogenic according to our data. Variant chr18-58390667-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 linkuse as main transcript	c.2677G>A	p.Glu893Lys	missense_variant	29/31	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8 linkuse as main transcript	c.2677G>A	p.Glu893Lys	missense_variant	29/31	1	NM_001144967.3	ENSP00000383199	P3	Q96PU5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1439208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713364

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Periventricular nodular heterotopia 7

Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Sep 01, 2024	- -
Pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The first report of this variant was in PMID: 27694961 and PMID: 28515470. Our patient was described in PMID: 34087865. This 2-year-old boy was polystigmatized and showed significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The proband showed also other symptoms, outside PVNH7 symptomatology, that were also present in the proband’s older brother (such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus). Brother did not carry the variant; thus, these symptoms are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2021	This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 873 of the NEDD4L protein (p.Glu873Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This missense change has been observed in individual(s) with NEDD4L-related conditions (PMID: 27694961, 28515470; Invitae). 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: 225191). This variant is also known as c.2677G>A p.Glu893Lys. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2024	Published functional studies demonstrate a damaging effect: decrease in protein stability and increased Akt phosphorylation (PMID: 27694961); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.2677G>A p.(Glu893Lys); This variant is associated with the following publications: (PMID: 31028281, 28515470, 27694961, 34087865, 35599849, 36934385) -

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 03, 2016

- -

Chromosome 5Q14.3 deletion syndrome, distal

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 02, 2024

Criteria applied: PS2,PS4_MOD,PM2_SUP,PP2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.88

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

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.7

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

REVEL

Uncertain

0.60

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

0.97

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

Vest4

0.77

MutPred

0.76

.;Gain of MoRF binding (P = 0.003);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.83

MPC

2.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.83

gMVP

0.89

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