rs879255597

chr18-58390667-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

The NM_001144967.3(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 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:8 U:1
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 7 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, 0.883
• PP5: Variant 18-58390667-G-A is Pathogenic according to our data. Variant chr18-58390667-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225191.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.2677G>A	p.Glu893Lys	missense_variant	29/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2677G>A	p.Glu893Lys	missense_variant	29/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1439208 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Periventricular nodular heterotopia 7 Pathogenic:4 Uncertain:1

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, 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
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	Invitae	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	Aug 29, 2021	Published functional studies demonstrate a damaging effect: decrease in protein stability and increased Akt phosphorylation (Broix et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28515470, 27694961, 34087865, 31028281) -

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	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;.;D;D;D;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
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	D
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

Other links and lift over

dbSNP: rs879255597; hg19: chr18-56057899; COSMIC: COSV56842960; COSMIC: COSV56842960;