18-58388540-C-T

Position:

• chr18-58388540-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.2548-545C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,326 control chromosomes in the GnomAD database, including 1,223 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 0.11 (1223 hom., cov: 32)
  • Exomes 𝑓: 0.11 (0 hom.)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250

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 (SAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.2548-545C>T		intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2548-545C>T		intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17303 AN: 152096 Hom.: 1223 Cov.: 32

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0509

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.109 AC: 12 AN: 110 Hom.: 0 Cov.: 0 AF XY: 0.107 AC XY: 6 AN XY: 56

Gnomad4 AMR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.114 AC: 17299 AN: 152216 Hom.: 1223 Cov.: 32 AF XY: 0.120 AC XY: 8902 AN XY: 74402

Gnomad4 AFR AF: 0.0821

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.0512

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.0899

Alfa AF: 0.120 Hom.: 1756

Bravo AF: 0.0967

Asia WGS AF: 0.125 AC: 436 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	3.0
DANN	Benign	0.80

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: rs2043265; hg19: chr18-56055772;