rs12906245

Positions:

• chr15-55838491-T-A
• chr15-55838491-T-G

Variant summary

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

The NM_006154.4(NEDD4):​c.2127+18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,541,996 control chromosomes in the GnomAD database, including 6,304 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 0.074 (478 hom., cov: 33)
  • Exomes 𝑓: 0.088 (5826 hom.)
• Consequence: NEDD4 NM_006154.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57

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=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4	NM_006154.4	c.2127+18A>T		intron_variant		ENST00000435532.8	NP_006145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8	c.2127+18A>T		intron_variant		1	NM_006154.4	ENSP00000410613	P1

Frequencies

GnomAD3 genomes AF: 0.0737 AC: 11217 AN: 152156 Hom.: 473 Cov.: 33

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0792

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0803

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.0659

GnomAD3 exomes AF: 0.0762 AC: 19030 AN: 249722 Hom.: 925 AF XY: 0.0756 AC XY: 10215 AN XY: 135112

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.0730

Gnomad ASJ exome AF: 0.0940

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.0485

Gnomad FIN exome AF: 0.0809

Gnomad NFE exome AF: 0.0996

Gnomad OTH exome AF: 0.0753

GnomAD4 exome AF: 0.0875 AC: 121658 AN: 1389722 Hom.: 5826 Cov.: 24 AF XY: 0.0867 AC XY: 60295 AN XY: 695646

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.0725

Gnomad4 ASJ exome AF: 0.0936

Gnomad4 EAS exome AF: 0.00352

Gnomad4 SAS exome AF: 0.0491

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.0968

Gnomad4 OTH exome AF: 0.0795

GnomAD4 genome AF: 0.0738 AC: 11240 AN: 152274 Hom.: 478 Cov.: 33 AF XY: 0.0726 AC XY: 5404 AN XY: 74462

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.0794

Gnomad4 ASJ AF: 0.0855

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.0512

Gnomad4 FIN AF: 0.0803

Gnomad4 NFE AF: 0.0992

Gnomad4 OTH AF: 0.0652

Alfa AF: 0.0869 Hom.: 119

Bravo AF: 0.0701

Asia WGS AF: 0.0430 AC: 148 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.27
DANN	Benign	0.70

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: rs12906245; hg19: chr15-56130689;