rs4941304

Positions:

• chr18-58064960-T-C

Variant summary

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

The NM_001144967.3(NEDD4L):​c.48+20252T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,022 control chromosomes in the GnomAD database, including 38,374 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 0.70 (38374 hom., cov: 31)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610

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 (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.48+20252T>C		intron_variant		ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.48+20252T>C		intron_variant		1	NM_001144967.3	ENSP00000383199	P3

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106811 AN: 151904 Hom.: 38351 Cov.: 31

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.738

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

GnomAD4 genome AF: 0.703 AC: 106885 AN: 152022 Hom.: 38374 Cov.: 31 AF XY: 0.711 AC XY: 52866 AN XY: 74322

Gnomad4 AFR AF: 0.546

Gnomad4 AMR AF: 0.782

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.869

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.773

Gnomad4 NFE AF: 0.741

Gnomad4 OTH AF: 0.741

Alfa AF: 0.745 Hom.: 55841

Bravo AF: 0.700

Asia WGS AF: 0.846 AC: 2945 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.23

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: rs4941304; hg19: chr18-55732192;