rs6493829

Positions:

• chr15-55966611-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006154.4(NEDD4):​c.46-65T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 675,640 control chromosomes in the GnomAD database, including 98,259 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 0.54 (22400 hom., cov: 31)
  • Exomes 𝑓: 0.53 (75859 hom.)
• Consequence: NEDD4 NM_006154.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4	NM_006154.4	c.46-65T>A		intron_variant		ENST00000435532.8	NP_006145.2
NEDD4	NM_001329212.2	c.-421-65T>A		intron_variant			NP_001316141.1
NEDD4	XM_011521625.4	c.-108-65T>A		intron_variant			XP_011519927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8	c.46-65T>A		intron_variant		1	NM_006154.4	ENSP00000410613.3
NEDD4	ENST00000502612.5	n.37-65T>A		intron_variant		3		ENSP00000424471.1
NEDD4	ENST00000648451.1	n.46-65T>A		intron_variant				ENSP00000498181.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 81895 AN: 151514 Hom.: 22350 Cov.: 31

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.522

GnomAD4 exome AF: 0.528 AC: 276845 AN: 524008 Hom.: 75859 AF XY: 0.528 AC XY: 144440 AN XY: 273324

Gnomad4 AFR exome AF: 0.504

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.328

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.573

Gnomad4 NFE exome AF: 0.545

Gnomad4 OTH exome AF: 0.530

GnomAD4 genome AF: 0.541 AC: 82008 AN: 151632 Hom.: 22400 Cov.: 31 AF XY: 0.536 AC XY: 39728 AN XY: 74118

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.514

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.522

Alfa AF: 0.552 Hom.: 2900

Bravo AF: 0.538

Asia WGS AF: 0.430 AC: 1476 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.1
DANN	Benign	0.87

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: rs6493829; hg19: chr15-56258809; COSMIC: COSV71074717; COSMIC: COSV71074717;