rs292449

Positions:

• chr18-58227849-G-C

Variant summary

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

The NM_001144971.2(NEDD4L):​c.-300G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 971,740 control chromosomes in the GnomAD database, including 62,522 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 0.42 (14345 hom., cov: 32)
  • Exomes 𝑓: 0.34 (48177 hom.)
• Consequence: NEDD4L NM_001144971.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.970

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]

NEDD4L (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.123-17578G>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.123-17578G>C		intron_variant		1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63898 AN: 151886 Hom.: 14303 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.337 AC: 276293 AN: 819736 Hom.: 48177 Cov.: 18 AF XY: 0.338 AC XY: 127935 AN XY: 378804

Gnomad4 AFR exome AF: 0.525

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.807

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.376

GnomAD4 genome AF: 0.421 AC: 63996 AN: 152004 Hom.: 14345 Cov.: 32 AF XY: 0.423 AC XY: 31441 AN XY: 74304

Gnomad4 AFR AF: 0.514

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.812

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.455

Alfa AF: 0.381 Hom.: 1421

Bravo AF: 0.444

Asia WGS AF: 0.606 AC: 2108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Benign	0.80

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: rs292449; hg19: chr18-55895081;