Genetic Variant NEDD4:p.Arg260Gln (chr15-55860674-C-T) – 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.779G>A(p.Arg260Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,613,792 control chromosomes in the GnomAD database, including 483,288 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.72 ( 40014 hom., cov: 33)

Exomes 𝑓: 0.78 ( 443274 hom. )

Consequence

NEDD4
NM_006154.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

49 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 (MetaRNN=1.0891531E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4	NM_006154.4 link	c.779G>A	p.Arg260Gln	missense_variant	Exon 10 of 29	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.779G>A	p.Arg260Gln	missense_variant	Exon 10 of 29	1	NM_006154.4	ENSP00000410613.3		P46934-4

Frequencies

GnomAD3 genomes

AF:

0.721

AC:

109554

AN:

152024

Hom.:

40004

Cov.:

show subpopulations

Gnomad AFR

AF:

0.612

Gnomad AMI

AF:

0.843

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.802

Gnomad EAS

AF:

0.598

Gnomad SAS

AF:

0.757

Gnomad FIN

AF:

0.713

Gnomad MID

AF:

0.725

Gnomad NFE

AF:

0.797

Gnomad OTH

AF:

0.698

GnomAD2 exomes

AF:

0.738

AC:

185428

AN:

251290

AF XY:

0.746

show subpopulations

Gnomad AFR exome

AF:

0.607

Gnomad AMR exome

AF:

0.667

Gnomad ASJ exome

AF:

0.793

Gnomad EAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.717

Gnomad NFE exome

AF:

0.796

Gnomad OTH exome

AF:

0.749

GnomAD4 exome

AF:

0.777

AC:

1135572

AN:

1461650

Hom.:

443274

Cov.:

AF XY:

0.777

AC XY:

565326

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.603

AC:

20193

AN:

33472

American (AMR)

AF:

0.664

AC:

29695

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.792

AC:

20702

AN:

26132

East Asian (EAS)

AF:

0.600

AC:

23833

AN:

39700

South Asian (SAS)

AF:

0.758

AC:

65344

AN:

86252

European-Finnish (FIN)

AF:

0.720

AC:

38473

AN:

53420

Middle Eastern (MID)

AF:

0.719

AC:

4150

AN:

5768

European-Non Finnish (NFE)

AF:

0.799

AC:

887921

AN:

1111806

Other (OTH)

AF:

0.749

AC:

45261

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

13096

26193

39289

52386

65482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20708

41416

62124

82832

103540

<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:

0.721

AC:

109619

AN:

152142

Hom.:

40014

Cov.:

AF XY:

0.717

AC XY:

53358

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.612

AC:

25405

AN:

41482

American (AMR)

AF:

0.688

AC:

10496

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.802

AC:

2783

AN:

3470

East Asian (EAS)

AF:

0.598

AC:

3098

AN:

5178

South Asian (SAS)

AF:

0.757

AC:

3651

AN:

4826

European-Finnish (FIN)

AF:

0.713

AC:

7550

AN:

10588

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.797

AC:

54187

AN:

68014

Other (OTH)

AF:

0.697

AC:

1473

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1591

3183

4774

6366

7957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.761

Hom.:

130733

Bravo

AF:

0.709

TwinsUK

AF:

0.811

AC:

3007

ALSPAC

AF:

0.796

AC:

3067

ESP6500AA

AF:

0.613

AC:

2690

ESP6500EA

AF:

0.796

AC:

6829

ExAC

AF:

0.741

AC:

89989

Asia WGS

AF:

0.671

AC:

2336

AN:

3478

EpiCase

AF:

0.796

EpiControl

AF:

0.781

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

T;T;T;T

MetaRNN

Benign

0.0000011

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

.;M;.;.

PhyloP100

2.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.94

N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.099

T;D;T;D

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.74

P;P;B;P

Vest4

0.13

MPC

0.060

ClinPred

0.0064

GERP RS

2.8

Varity_R

0.076

gMVP

0.35

Mutation Taster

=93/7

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