18-58316132-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001144967.3(NEDD4L):c.348+100A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 973,444 control chromosomes in the GnomAD database, including 21,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (5346 hom., cov: 32)
  • Exomes 𝑓: 0.19 (16467 hom.)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.283

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-58316132-A-G is Benign according to our data. Variant chr18-58316132-A-G is described in ClinVar as [Benign]. Clinvar id is 1254207.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.348+100A>G		intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.348+100A>G		intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37167 AN: 151958 Hom.: 5326 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.192 AC: 157998 AN: 821366 Hom.: 16467 AF XY: 0.189 AC XY: 80770 AN XY: 426488

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.245 AC: 37234 AN: 152078 Hom.: 5346 Cov.: 32 AF XY: 0.240 AC XY: 17815 AN XY: 74334

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.244

Alfa AF: 0.193 Hom.: 4972

Bravo AF: 0.266

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.9
Dann	Benign	0.72

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: rs2288775; hg19: chr18-55983364; COSMIC: COSV56842844; COSMIC: COSV56842844;