rs4149601

chr18-58149559-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000357895.9(NEDD4L):c.24G>A(p.Gln8=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,541,682 control chromosomes in the GnomAD database, including 82,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8096 hom., cov: 33)
  • Exomes 𝑓: 0.32 (73942 hom.)
• Consequence: NEDD4L ENST00000357895.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001359
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.453

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-58149559-G-A is Benign according to our data. Variant chr18-58149559-G-A is described in ClinVar as [Benign]. Clinvar id is 225996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.49-16229G>A		intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.49-16229G>A		intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48814 AN: 151970 Hom.: 8088 Cov.: 33

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.282 AC: 43330 AN: 153806 Hom.: 6728 AF XY: 0.281 AC XY: 22967 AN XY: 81616

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.321 AC: 446018 AN: 1389594 Hom.: 73942 Cov.: 27 AF XY: 0.318 AC XY: 218055 AN XY: 686008

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.316

GnomAD4 genome AF: 0.321 AC: 48849 AN: 152088 Hom.: 8096 Cov.: 33 AF XY: 0.318 AC XY: 23623 AN XY: 74352

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.327

Alfa AF: 0.329 Hom.: 15069

Bravo AF: 0.320

Asia WGS AF: 0.204 AC: 711 AN: 3478

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	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	This variant is associated with the following publications: (PMID: 16103266, 16788695, 12522688, 21052022, 19635985, 19364400) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.9
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.070		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: rs4149601; hg19: chr18-55816791; COSMIC: COSV56843798;