Variant rs4149601 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000357895.9(NEDD4L):c.24G>A(p.Gln8=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,541,682 control chromosomes in the GnomAD database, including 82,038 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 Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8096 hom., cov: 33)

Exomes 𝑓: 0.32 ( 73942 hom. )

Consequence

NEDD4L
ENST00000357895.9 splice_region, synonymous

Scores

Splicing: ADA: 0.0001359

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.453

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 18-58149559-G-A is Benign according to our data. Variant chr18-58149559-G-A is described in ClinVar as [Benign]. Clinvar id is 225996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.453 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 linkuse as main transcript	c.49-16229G>A		intron_variant		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.49-16229G>A		intron_variant		1	NM_001144967.3	ENSP00000383199	P3	Q96PU5-1

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48814

AN:

151970

Hom.:

8088

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.410

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.333

GnomAD3 exomes

AF:

0.282

AC:

43330

AN:

153806

Hom.:

6728

AF XY:

0.281

AC XY:

22967

AN XY:

81616

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.224

Gnomad SAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.315

Gnomad NFE exome

AF:

0.333

Gnomad OTH exome

AF:

0.312

GnomAD4 exome

AF:

0.321

AC:

446018

AN:

1389594

Hom.:

73942

Cov.:

AF XY:

0.318

AC XY:

218055

AN XY:

686008

show subpopulations

Gnomad4 AFR exome

AF:

0.353

Gnomad4 AMR exome

AF:

0.184

Gnomad4 ASJ exome

AF:

0.411

Gnomad4 EAS exome

AF:

0.169

Gnomad4 SAS exome

AF:

0.197

Gnomad4 FIN exome

AF:

0.311

Gnomad4 NFE exome

AF:

0.337

Gnomad4 OTH exome

AF:

0.316

GnomAD4 genome

AF:

0.321

AC:

48849

AN:

152088

Hom.:

8096

Cov.:

AF XY:

0.318

AC XY:

23623

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.345

Gnomad4 AMR

AF:

0.263

Gnomad4 ASJ

AF:

0.410

Gnomad4 EAS

AF:

0.202

Gnomad4 SAS

AF:

0.190

Gnomad4 FIN

AF:

0.308

Gnomad4 NFE

AF:

0.335

Gnomad4 OTH

AF:

0.327

Alfa

AF:

0.329

Hom.:

15069

Bravo

AF:

0.320

Asia WGS

AF:

0.204

AC:

711

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	This variant is associated with the following publications: (PMID: 16103266, 16788695, 12522688, 21052022, 19635985, 19364400) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.9

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.070

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