dbSNP rs1912403: NEDD4:p.Met33Val (chr15-55916735-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000508342.5(NEDD4):c.97A>G(p.Met33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,614,000 control chromosomes in the GnomAD database, including 6,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 435 hom., cov: 32)

Exomes 𝑓: 0.087 ( 6059 hom. )

Consequence

NEDD4
ENST00000508342.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.61

Publications

26 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016183257).

BP6

Variant 15-55916735-T-C is Benign according to our data. Variant chr15-55916735-T-C is described in ClinVar as Benign. ClinVar VariationId is 1296895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4	NM_006154.4 link	c.291+7911A>G		intron_variant	Intron 5 of 28	ENST00000435532.8	NP_006145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8 link	c.291+7911A>G		intron_variant	Intron 5 of 28	1	NM_006154.4	ENSP00000410613.3

Frequencies

GnomAD3 genomes

AF:

0.0663

AC:

10087

AN:

152136

Hom.:

435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0706

Gnomad ASJ

AF:

0.0848

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0484

Gnomad FIN

AF:

0.0809

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0985

Gnomad OTH

AF:

0.0565

GnomAD2 exomes

AF:

0.0738

AC:

18557

AN:

251418

AF XY:

0.0736

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.0695

Gnomad ASJ exome

AF:

0.0927

Gnomad EAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.0822

Gnomad NFE exome

AF:

0.0989

Gnomad OTH exome

AF:

0.0735

GnomAD4 exome

AF:

0.0872

AC:

127411

AN:

1461746

Hom.:

6059

Cov.:

AF XY:

0.0863

AC XY:

62734

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0147

AC:

491

AN:

33474

American (AMR)

AF:

0.0679

AC:

3035

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0928

AC:

2425

AN:

26126

East Asian (EAS)

AF:

0.00156

AC:

AN:

39698

South Asian (SAS)

AF:

0.0479

AC:

4130

AN:

86252

European-Finnish (FIN)

AF:

0.0847

AC:

4527

AN:

53418

Middle Eastern (MID)

AF:

0.0402

AC:

232

AN:

5768

European-Non Finnish (NFE)

AF:

0.0970

AC:

107821

AN:

1111894

Other (OTH)

AF:

0.0776

AC:

4688

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

7186

14372

21558

28744

35930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3786

7572

11358

15144

18930

<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:

0.0663

AC:

10091

AN:

152254

Hom.:

435

Cov.:

AF XY:

0.0646

AC XY:

4811

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0171

AC:

712

AN:

41576

American (AMR)

AF:

0.0709

AC:

1083

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

294

AN:

3466

East Asian (EAS)

AF:

0.00154

AC:

AN:

5184

South Asian (SAS)

AF:

0.0485

AC:

234

AN:

4828

European-Finnish (FIN)

AF:

0.0809

AC:

859

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0986

AC:

6700

AN:

67984

Other (OTH)

AF:

0.0559

AC:

118

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

482

964

1445

1927

2409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0844

Hom.:

2209

Bravo

AF:

0.0612

TwinsUK

AF:

0.0976

AC:

362

ALSPAC

AF:

0.0960

AC:

370

ESP6500AA

AF:

0.0164

AC:

ESP6500EA

AF:

0.0907

AC:

778

ExAC

AF:

0.0738

AC:

8965

Asia WGS

AF:

0.0390

AC:

134

AN:

3478

EpiCase

AF:

0.0885

EpiControl

AF:

0.0883

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

Jan 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30180840)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0

.;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.21

N;N;N

REVEL

Benign

0.053

Sift

Benign

0.045

D;T;T

Sift4G

Uncertain

0.010

D;D;D

Vest4

0.12

ClinPred

0.0065

GERP RS

4.0

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.085

gMVP

0.32

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over