Genetic Variant NEDD4:c.2527+71G>T (chr15-55832937-C-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.2527+71G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,010,904 control chromosomes in the GnomAD database, including 56,698 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 0.33 ( 8340 hom., cov: 32)

Exomes 𝑓: 0.33 ( 48358 hom. )

Consequence

NEDD4
NM_006154.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.738

Publications

10 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=-0.94).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006154.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEDD4	NM_006154.4	MANE Select	c.2527+71G>T	intron	N/A	NP_006145.2	P46934-4
NEDD4	NM_001284338.2		c.3784+71G>T	intron	N/A	NP_001271267.1	P46934-1
NEDD4	NM_001284339.1		c.3736+71G>T	intron	N/A	NP_001271268.1	P46934-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEDD4	ENST00000435532.8	TSL:1 MANE Select	c.2527+71G>T	intron	N/A	ENSP00000410613.3	P46934-4
NEDD4	ENST00000508342.5	TSL:1	c.3784+71G>T	intron	N/A	ENSP00000424827.1	P46934-1
NEDD4	ENST00000506154.1	TSL:1	c.3736+71G>T	intron	N/A	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49848

AN:

151770

Hom.:

8342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.336

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.325

Gnomad OTH

AF:

0.306

GnomAD4 exome

AF:

0.332

AC:

285515

AN:

859016

Hom.:

48358

AF XY:

0.335

AC XY:

148500

AN XY:

443556

show subpopulations

African (AFR)

AF:

0.344

AC:

7122

AN:

20692

American (AMR)

AF:

0.344

AC:

11105

AN:

32238

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

4981

AN:

19132

East Asian (EAS)

AF:

0.340

AC:

12375

AN:

36388

South Asian (SAS)

AF:

0.431

AC:

26536

AN:

61636

European-Finnish (FIN)

AF:

0.311

AC:

14908

AN:

48000

Middle Eastern (MID)

AF:

0.320

AC:

1410

AN:

4410

European-Non Finnish (NFE)

AF:

0.326

AC:

194399

AN:

597034

Other (OTH)

AF:

0.321

AC:

12679

AN:

39486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

9127

18254

27381

36508

45635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4892

9784

14676

19568

24460

<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:

0.328

AC:

49858

AN:

151888

Hom.:

8340

Cov.:

AF XY:

0.330

AC XY:

24471

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.336

AC:

13889

AN:

41362

American (AMR)

AF:

0.326

AC:

4986

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

913

AN:

3470

East Asian (EAS)

AF:

0.324

AC:

1672

AN:

5158

South Asian (SAS)

AF:

0.427

AC:

2052

AN:

4810

European-Finnish (FIN)

AF:

0.305

AC:

3210

AN:

10512

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.325

AC:

22107

AN:

67978

Other (OTH)

AF:

0.305

AC:

645

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1695

3391

5086

6782

8477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.223

Hom.:

589

Bravo

AF:

0.324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

3.7

(source)

DANN

Benign

0.45

PhyloP100

0.74

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over