chr18-58390748-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001144967.3(NEDD4L):c.2752+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,573,436 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 32)

Exomes 𝑓: 0.013 ( 190 hom. )

Consequence

NEDD4L
NM_001144967.3 splice_region, intron

Scores

Splicing: ADA: 0.0001561

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.405

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 18-58390748-C-T is Benign according to our data. Variant chr18-58390748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-58390748-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.011 (1668/152240) while in subpopulation SAS AF= 0.032 (154/4816). AF 95% confidence interval is 0.0279. There are 17 homozygotes in gnomad4. There are 876 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.2752+6C>T		splice_region_variant, intron_variant	Intron 29 of 30	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.2752+6C>T		splice_region_variant, intron_variant	Intron 29 of 30	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1669

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0322

Gnomad FIN

AF:

0.0286

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0139

AC:

2810

AN:

202232

Hom.:

AF XY:

0.0153

AC XY:

1655

AN XY:

107886

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00381

Gnomad ASJ exome

AF:

0.00888

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0333

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0133

AC:

18966

AN:

1421196

Hom.:

190

Cov.:

AF XY:

0.0142

AC XY:

9980

AN XY:

704514

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00432

Gnomad4 ASJ exome

AF:

0.00886

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0340

Gnomad4 FIN exome

AF:

0.0295

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.0110

AC:

1668

AN:

152240

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

876

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0320

Gnomad4 FIN

AF:

0.0286

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00796

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEDD4L-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.030

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