chr18-58044635-C-T

Position:

• chr18-58044635-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144967.3(NEDD4L):​c.-26C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,593,310 control chromosomes in the GnomAD database, including 3,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (457 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2803 hom.)
• Consequence: NEDD4L NM_001144967.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.849

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 18-58044635-C-T is Benign according to our data. Variant chr18-58044635-C-T is described in ClinVar as [Benign]. Clinvar id is 1282456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.-26C>T		5_prime_UTR_variant	1/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.-26C>T		5_prime_UTR_variant	1/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10870 AN: 151958 Hom.: 459 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0612

Gnomad OTH AF: 0.0666

GnomAD3 exomes AF: 0.0508 AC: 11224 AN: 220872 Hom.: 369 AF XY: 0.0506 AC XY: 6188 AN XY: 122372

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.0000641

Gnomad SAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0539

Gnomad NFE exome AF: 0.0619

Gnomad OTH exome AF: 0.0549

GnomAD4 exome AF: 0.0593 AC: 85418 AN: 1441240 Hom.: 2803 Cov.: 31 AF XY: 0.0585 AC XY: 41938 AN XY: 716502

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0410

Gnomad4 EAS exome AF: 0.0000794

Gnomad4 SAS exome AF: 0.0394

Gnomad4 FIN exome AF: 0.0562

Gnomad4 NFE exome AF: 0.0627

Gnomad4 OTH exome AF: 0.0607

GnomAD4 genome AF: 0.0715 AC: 10875 AN: 152070 Hom.: 457 Cov.: 32 AF XY: 0.0692 AC XY: 5146 AN XY: 74342

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.0373

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.0612

Gnomad4 OTH AF: 0.0659

Alfa AF: 0.0351 Hom.: 26

Bravo AF: 0.0737

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.9
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113358301; hg19: chr18-55711867;