18-58329012-C-T

Position:

chr18-58329012-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001144967.3(NEDD4L):c.698C>T(p.Ser233Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00458 in 1,613,978 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 29 hom. )

Consequence

NEDD4L
NM_001144967.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.06

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074940026).

BP6

Variant 18-58329012-C-T is Benign according to our data. Variant chr18-58329012-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 417001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 536 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.698C>T	p.Ser233Leu	missense_variant	10/31	ENST00000400345.8	NP_001138439.1	Q96PU5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8 link	c.698C>T	p.Ser233Leu	missense_variant	10/31	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

536

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00391

AC:

974

AN:

249130

Hom.:

AF XY:

0.00416

AC XY:

563

AN XY:

135210

show subpopulations

Gnomad AFR exome

AF:

0.000647

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00904

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00458

Gnomad FIN exome

AF:

0.00562

Gnomad NFE exome

AF:

0.00478

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00470

AC:

6863

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00483

AC XY:

3510

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00807

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00473

Gnomad4 FIN exome

AF:

0.00519

Gnomad4 NFE exome

AF:

0.00497

Gnomad4 OTH exome

AF:

0.00487

GnomAD4 genome

AF:

0.00352

AC:

536

AN:

152320

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00565

Gnomad4 NFE

AF:

0.00532

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00492

Hom.:

Bravo

AF:

0.00313

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.00592

AC:

ExAC

AF:

0.00409

AC:

495

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NEDD4L: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 27694961, 25542253, 17331106) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

NEDD4L-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Periventricular nodular heterotopia 7

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

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

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

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

M_CAP

Benign

0.018

MetaRNN

Benign

0.0075

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;L;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;N;N;N;D;N;N;.;N;D;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.11

T;T;D;T;T;D;T;.;D;T;.;.;.

Sift4G

Benign

0.30

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

Polyphen

0.41

B;B;P;P;.;.;P;P;.;.;.;.;.

Vest4

0.57

MVP

0.35

MPC

0.45

ClinPred

0.020

GERP RS

6.2

Varity_R

0.079

gMVP

0.57

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