dbSNP rs12906245: NEDD4:c.2127+18A>T (chr15-55838491-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006154.4(NEDD4):c.2127+18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,541,996 control chromosomes in the GnomAD database, including 6,304 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.074 ( 478 hom., cov: 33)

Exomes 𝑓: 0.088 ( 5826 hom. )

Consequence

NEDD4
NM_006154.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.57

Publications

5 publications found

Variant links:

Genes affected

NEDD4 (HGNC:7727): (NEDD4 E3 ubiquitin protein ligase) This gene is the founding member of the NEDD4 family of HECT ubiquitin ligases that function in the ubiquitin proteasome system of protein degradation. The encoded protein contains an N-terminal calcium and phospholipid binding C2 domain followed by multiple tryptophan-rich WW domains and, a C-terminal HECT ubiquitin ligase catalytic domain. It plays critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumor suppressor PTEN. [provided by RefSeq, Jul 2016]

NEDD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4	NM_006154.4 link	c.2127+18A>T		intron_variant	Intron 22 of 28	ENST00000435532.8	NP_006145.2	P46934-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8 link	c.2127+18A>T		intron_variant	Intron 22 of 28	1	NM_006154.4	ENSP00000410613.3		P46934-4

Frequencies

GnomAD3 genomes

AF:

0.0737

AC:

11217

AN:

152156

Hom.:

473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0792

Gnomad ASJ

AF:

0.0855

Gnomad EAS

AF:

0.00423

Gnomad SAS

AF:

0.0513

Gnomad FIN

AF:

0.0803

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0992

Gnomad OTH

AF:

0.0659

GnomAD2 exomes

AF:

0.0762

AC:

19030

AN:

249722

AF XY:

0.0756

show subpopulations

Gnomad AFR exome

AF:

0.0372

Gnomad AMR exome

AF:

0.0730

Gnomad ASJ exome

AF:

0.0940

Gnomad EAS exome

AF:

0.00359

Gnomad FIN exome

AF:

0.0809

Gnomad NFE exome

AF:

0.0996

Gnomad OTH exome

AF:

0.0753

GnomAD4 exome

AF:

0.0875

AC:

121658

AN:

1389722

Hom.:

5826

Cov.:

AF XY:

0.0867

AC XY:

60295

AN XY:

695646

show subpopulations

African (AFR)

AF:

0.0367

AC:

1175

AN:

31994

American (AMR)

AF:

0.0725

AC:

3225

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

2405

AN:

25704

East Asian (EAS)

AF:

0.00352

AC:

138

AN:

39232

South Asian (SAS)

AF:

0.0491

AC:

4162

AN:

84814

European-Finnish (FIN)

AF:

0.0829

AC:

4321

AN:

52094

Middle Eastern (MID)

AF:

0.0419

AC:

236

AN:

5638

European-Non Finnish (NFE)

AF:

0.0968

AC:

101389

AN:

1047784

Other (OTH)

AF:

0.0795

AC:

4607

AN:

57964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

5199

10398

15598

20797

25996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3468

6936

10404

13872

17340

<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:

0.0738

AC:

11240

AN:

152274

Hom.:

478

Cov.:

AF XY:

0.0726

AC XY:

5404

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0395

AC:

1641

AN:

41566

American (AMR)

AF:

0.0794

AC:

1214

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

297

AN:

3472

East Asian (EAS)

AF:

0.00424

AC:

AN:

5192

South Asian (SAS)

AF:

0.0512

AC:

247

AN:

4828

European-Finnish (FIN)

AF:

0.0803

AC:

852

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0992

AC:

6745

AN:

68008

Other (OTH)

AF:

0.0652

AC:

138

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

534

1068

1601

2135

2669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0869

Hom.:

119

Bravo

AF:

0.0701

Asia WGS

AF:

0.0430

AC:

148

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.27

(source)

DANN

Benign

0.70

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over