rs112196694

Positions:

• chr18-58389201-G-A

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.2655+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,603,368 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (130 hom.)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.337

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=-0.91).
• BP6: Variant 18-58389201-G-A is Benign according to our data. Variant chr18-58389201-G-A is described in ClinVar as [Benign]. Clinvar id is 417009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.2655+9G>A		intron_variant		ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2655+9G>A		intron_variant		1	NM_001144967.3	ENSP00000383199	P3

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3586 AN: 152172 Hom.: 133 Cov.: 33

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00645 AC: 1587 AN: 245898 Hom.: 58 AF XY: 0.00492 AC XY: 657 AN XY: 133522

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00253

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00275 AC: 3990 AN: 1451078 Hom.: 130 Cov.: 27 AF XY: 0.00243 AC XY: 1753 AN XY: 721826

Gnomad4 AFR exome AF: 0.0817

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.00670

GnomAD4 genome AF: 0.0236 AC: 3599 AN: 152290 Hom.: 133 Cov.: 33 AF XY: 0.0225 AC XY: 1678 AN XY: 74476

Gnomad4 AFR AF: 0.0787

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0142 Hom.: 31

Bravo AF: 0.0276

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.73
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: rs112196694; hg19: chr18-56056433;