rs6493829

Variant names:

• chr15-55966611-A-T
• rs6493829
• NM_006154.4:c.46-65T>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
NEDD4	NM_006154.4	c.46-65T>A		intron_variant	Intron 1 of 28	ENST00000435532.8	NP_006145.2
NEDD4	NM_001329212.2	c.-421-65T>A		intron_variant	Intron 1 of 28		NP_001316141.1
NEDD4	XM_011521625.4	c.-108-65T>A		intron_variant	Intron 2 of 29		XP_011519927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8	c.46-65T>A		intron_variant	Intron 1 of 28	1	NM_006154.4	ENSP00000410613.3
NEDD4	ENST00000502612.5	n.37-65T>A		intron_variant	Intron 1 of 8	3		ENSP00000424471.1
NEDD4	ENST00000648451.1	n.46-65T>A		intron_variant	Intron 1 of 28			ENSP00000498181.1
NEDD4	ENST00000513957.1	n.-65T>A		upstream_gene_variant		2

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

African (AFR) AF: 0.504 AC: 5940 AN: 11796

American (AMR) AF: 0.509 AC: 6677 AN: 13126

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 8390 AN: 14994

East Asian (EAS) AF: 0.328 AC: 8828 AN: 26946

South Asian (SAS) AF: 0.456 AC: 14100 AN: 30928

European-Finnish (FIN) AF: 0.573 AC: 23680 AN: 41360

Middle Eastern (MID) AF: 0.454 AC: 1108 AN: 2442

European-Non Finnish (NFE) AF: 0.545 AC: 194009 AN: 355786

Other (OTH) AF: 0.530 AC: 14113 AN: 26630

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

African (AFR) AF: 0.529 AC: 21876 AN: 41338

American (AMR) AF: 0.514 AC: 7829 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1958 AN: 3472

East Asian (EAS) AF: 0.357 AC: 1840 AN: 5158

South Asian (SAS) AF: 0.473 AC: 2277 AN: 4816

European-Finnish (FIN) AF: 0.578 AC: 6018 AN: 10414

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.566 AC: 38421 AN: 67896

Other (OTH) AF: 0.522 AC: 1099 AN: 2104

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
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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