rs878396

Positions:

• chr18-58143826-G-A
• chr18-58143826-G-T

Variant summary

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

The NM_001144967.3(NEDD4L):​c.49-21962G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,014 control chromosomes in the GnomAD database, including 4,728 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 0.25 (4728 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

Genes affected

NEDD4L (HGNC:7728): (NEDD4 like E3 ubiquitin protein ligase) This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.49-21962G>A		intron_variant		ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.49-21962G>A		intron_variant		1	NM_001144967.3	ENSP00000383199	P3

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37837 AN: 151896 Hom.: 4725 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.255

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.249 AC: 37865 AN: 152014 Hom.: 4728 Cov.: 32 AF XY: 0.245 AC XY: 18218 AN XY: 74324

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.258

Alfa AF: 0.251 Hom.: 9769

Bravo AF: 0.252

Asia WGS AF: 0.233 AC: 810 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.1
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878396; hg19: chr18-55811058;