Genetic Variant NEDD4L:c.348+100A>G (chr18-58316132-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001144967.3(NEDD4L):c.348+100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 973,444 control chromosomes in the GnomAD database, including 21,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5346 hom., cov: 32)

Exomes 𝑓: 0.19 ( 16467 hom. )

Consequence

NEDD4L
NM_001144967.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.283

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 18-58316132-A-G is Benign according to our data. Variant chr18-58316132-A-G is described in ClinVar as [Benign]. Clinvar id is 1254207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.348+100A>G		intron_variant	Intron 6 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.348+100A>G		intron_variant	Intron 6 of 30	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37167

AN:

151958

Hom.:

5326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.393

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.273

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.176

Gnomad OTH

AF:

0.239

GnomAD4 exome

AF:

0.192

AC:

157998

AN:

821366

Hom.:

16467

AF XY:

0.189

AC XY:

80770

AN XY:

426488

show subpopulations

Gnomad4 AFR exome

AF:

0.405

Gnomad4 AMR exome

AF:

0.284

Gnomad4 ASJ exome

AF:

0.260

Gnomad4 EAS exome

AF:

0.269

Gnomad4 SAS exome

AF:

0.162

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.180

Gnomad4 OTH exome

AF:

0.209

GnomAD4 genome

AF:

0.245

AC:

37234

AN:

152078

Hom.:

5346

Cov.:

AF XY:

0.240

AC XY:

17815

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.394

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.273

Gnomad4 EAS

AF:

0.290

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.110

Gnomad4 NFE

AF:

0.176

Gnomad4 OTH

AF:

0.244

Alfa

AF:

0.193

Hom.:

4972

Bravo

AF:

0.266

Asia WGS

AF:

0.274

AC:

951

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: 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

-0.79

CADD

Benign

5.9

DANN

Benign

0.72

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