rs158856

Variant names:

• chr18-58243291-C-T
• rs158856
• NM_001144967.3:c.123-2136C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001144967.3(NEDD4L):​c.123-2136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,128 control chromosomes in the GnomAD database, including 6,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6678 hom., cov: 33)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 6 publications found

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]

NEDD4L Gene-Disease associations (from GenCC):

• periventricular nodular heterotopia 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.123-2136C>T		intron_variant	Intron 2 of 30	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.123-2136C>T		intron_variant	Intron 2 of 30	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43739 AN: 152010 Hom.: 6666 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.331

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43757 AN: 152128 Hom.: 6678 Cov.: 33 AF XY: 0.284 AC XY: 21126 AN XY: 74364

African (AFR) AF: 0.175 AC: 7269 AN: 41524

American (AMR) AF: 0.317 AC: 4851 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1247 AN: 3470

East Asian (EAS) AF: 0.266 AC: 1377 AN: 5176

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4816

European-Finnish (FIN) AF: 0.302 AC: 3193 AN: 10560

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23504 AN: 67974

Other (OTH) AF: 0.328 AC: 692 AN: 2112

Alfa AF: 0.329 Hom.: 34683

Bravo AF: 0.289

Asia WGS AF: 0.222 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.083
DANN	Benign	0.79
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs158856; hg19: chr18-55910523;