rs4149601

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000357895.9(NEDD4L):c.24G>A(p.Gln8Gln) 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

Publications

92 publications found

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 Gene-Disease associations (from GenCC):

periventricular nodular heterotopia 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NEDD4L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.49-16229G>A		intron_variant	Intron 1 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.49-16229G>A		intron_variant	Intron 1 of 30	1	NM_001144967.3	ENSP00000383199.2		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

GnomAD2 exomes

AF:

0.282

AC:

43330

AN:

153806

AF XY:

0.281

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 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

African (AFR)

AF:

0.353

AC:

11084

AN:

31392

American (AMR)

AF:

0.184

AC:

6550

AN:

35648

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

10319

AN:

25100

East Asian (EAS)

AF:

0.169

AC:

6045

AN:

35680

South Asian (SAS)

AF:

0.197

AC:

15546

AN:

78940

European-Finnish (FIN)

AF:

0.311

AC:

15322

AN:

49246

Middle Eastern (MID)

AF:

0.344

AC:

1951

AN:

5676

European-Non Finnish (NFE)

AF:

0.337

AC:

360966

AN:

1070284

Other (OTH)

AF:

0.316

AC:

18235

AN:

57628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

13142

26283

39425

52566

65708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11666

23332

34998

46664

58330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.321

AC:

48849

AN:

152088

Hom.:

8096

Cov.:

AF XY:

0.318

AC XY:

23623

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.345

AC:

14292

AN:

41466

American (AMR)

AF:

0.263

AC:

4015

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.410

AC:

1422

AN:

3466

East Asian (EAS)

AF:

0.202

AC:

1049

AN:

5182

South Asian (SAS)

AF:

0.190

AC:

915

AN:

4818

European-Finnish (FIN)

AF:

0.308

AC:

3260

AN:

10576

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22760

AN:

67978

Other (OTH)

AF:

0.327

AC:

690

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1755

3510

5265

7020

8775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.327

Hom.:

31050

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16103266, 16788695, 12522688, 21052022, 19635985, 19364400) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.9

(source)

DANN

Benign

0.87

PhyloP100

0.45

PromoterAI

0.068

Neutral

(source)

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over