rs529445

Positions:

• chr18-58116265-C-A

Variant summary

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

The NM_001144967.3(NEDD4L):​c.49-49523C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,156 control chromosomes in the GnomAD database, including 6,332 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 0.26 (6332 hom., cov: 33)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.49-49523C>A		intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.49-49523C>A		intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39278 AN: 152038 Hom.: 6324 Cov.: 33

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.258 AC: 39319 AN: 152156 Hom.: 6332 Cov.: 33 AF XY: 0.257 AC XY: 19122 AN XY: 74392

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.0831

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.248

Alfa AF: 0.203 Hom.: 4692

Bravo AF: 0.267

Asia WGS AF: 0.193 AC: 672 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
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: rs529445; hg19: chr18-55783497;