rs1912403

chr15-55916735-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.066 (435 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6059 hom.)
• Consequence: NEDD4 ENST00000508342.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1296895.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
NEDD4	NM_006154.4	c.291+7911A>G		intron_variant		ENST00000435532.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4	ENST00000435532.8	c.291+7911A>G		intron_variant		1	NM_006154.4	P1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10087 AN: 152136 Hom.: 435 Cov.: 32

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

GnomAD3 exomes AF: 0.0738 AC: 18557 AN: 251418 Hom.: 892 AF XY: 0.0736 AC XY: 10008 AN XY: 135886

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 SAS exome AF: 0.0476

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.: 35 AF XY: 0.0863 AC XY: 62734 AN XY: 727176

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.0679

Gnomad4 ASJ exome AF: 0.0928

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.0479

Gnomad4 FIN exome AF: 0.0847

Gnomad4 NFE exome AF: 0.0970

Gnomad4 OTH exome AF: 0.0776

GnomAD4 genome AF: 0.0663 AC: 10091 AN: 152254 Hom.: 435 Cov.: 32 AF XY: 0.0646 AC XY: 4811 AN XY: 74462

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.0709

Gnomad4 ASJ AF: 0.0848

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0485

Gnomad4 FIN AF: 0.0809

Gnomad4 NFE AF: 0.0986

Gnomad4 OTH AF: 0.0559

Alfa AF: 0.0875 Hom.: 1603

Bravo AF: 0.0612

TwinsUK AF: 0.0976 AC: 362

ALSPAC AF: 0.0960 AC: 370

ESP6500AA AF: 0.0164 AC: 72

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2019

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	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.97
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.25	T
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
Polyphen		0.0040	B;B;B
Vest4		0.12
MPC		0.047
ClinPred		0.0065	T
GERP RS		4.0
Varity_R		0.085
gMVP		0.32

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

Other links and lift over

dbSNP: rs1912403; hg19: chr15-56208933; COSMIC: COSV59061712; COSMIC: COSV59061712;