Genetic Variant NEDD4:p.Ser349Ser (chr15-55915785-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001284338.2(NEDD4):c.1047G>A(p.Ser349Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,154 control chromosomes in the GnomAD database, including 60,512 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 0.24 ( 4889 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55623 hom. )

Consequence

NEDD4
NM_001284338.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.56

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP7

Synonymous conserved (PhyloP=-1.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4	NM_006154.4 link	c.291+8861G>A		intron_variant	Intron 5 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.291+8861G>A		intron_variant	Intron 5 of 28	1	NM_006154.4	ENSP00000410613.3		P46934-4

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36488

AN:

151874

Hom.:

4881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.189

Gnomad AMR

AF:

0.305

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.240

GnomAD3 exomes

AF:

0.264

AC:

65900

AN:

249958

Hom.:

9518

AF XY:

0.259

AC XY:

35122

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.339

Gnomad ASJ exome

AF:

0.374

Gnomad EAS exome

AF:

0.131

Gnomad SAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.324

Gnomad NFE exome

AF:

0.285

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.271

AC:

396051

AN:

1461162

Hom.:

55623

Cov.:

AF XY:

0.268

AC XY:

195147

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.120

Gnomad4 AMR exome

AF:

0.337

Gnomad4 ASJ exome

AF:

0.368

Gnomad4 EAS exome

AF:

0.138

Gnomad4 SAS exome

AF:

0.170

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.282

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.240

AC:

36521

AN:

151992

Hom.:

4889

Cov.:

AF XY:

0.241

AC XY:

17893

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.306

Gnomad4 ASJ

AF:

0.367

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.166

Gnomad4 FIN

AF:

0.327

Gnomad4 NFE

AF:

0.285

Gnomad4 OTH

AF:

0.240

Alfa

AF:

0.279

Hom.:

9459

Bravo

AF:

0.235

Asia WGS

AF:

0.178

AC:

618

AN:

3478

EpiCase

AF:

0.283

EpiControl

AF:

0.282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.027

DANN

Benign

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over