rs202008394

chr18-58325121-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001144967.3(NEDD4L):c.639C>T(p.Asn213=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000657 in 1,614,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: NEDD4L NM_001144967.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.85

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=-0.28).
• BP6: Variant 18-58325121-C-T is Benign according to our data. Variant chr18-58325121-C-T is described in ClinVar as [Benign]. Clinvar id is 241028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.639C>T	p.Asn213=	synonymous_variant	9/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.639C>T	p.Asn213=	synonymous_variant	9/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000529 AC: 132 AN: 249300 Hom.: 0 AF XY: 0.000547 AC XY: 74 AN XY: 135242

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000832

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000676 AC: 988 AN: 1461690 Hom.: 1 Cov.: 31 AF XY: 0.000652 AC XY: 474 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.000787

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74506

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000552

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000593

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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NEDD4L: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs202008394; hg19: chr18-55992353;