rs12454023

chr18-58342372-C-T

Variant summary

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

The NM_001144967.3(NEDD4L):c.1378-534C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 151,958 control chromosomes in the GnomAD database, including 17,779 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 0.47 (17779 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114

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 (EAS) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.1378-534C>T		intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.1378-534C>T		intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71790 AN: 151840 Hom.: 17776 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.652

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.466

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

GnomAD4 genome AF: 0.473 AC: 71820 AN: 151958 Hom.: 17779 Cov.: 32 AF XY: 0.484 AC XY: 35959 AN XY: 74272

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.524

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.660

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.465

Alfa AF: 0.495 Hom.: 12098

Bravo AF: 0.456

Asia WGS AF: 0.600 AC: 2089 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	3.8
Dann	Benign	0.69

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: rs12454023; hg19: chr18-56009604;