rs520210

Variant names:

• chr18-58140841-G-A
• rs520210
• NM_001144967.3:c.49-24947G>A

Variant summary

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

The NM_001144967.3(NEDD4L):​c.49-24947G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 152,132 control chromosomes in the GnomAD database, including 10,745 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 0.36 (10745 hom., cov: 33)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.709
• Publications: 9 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.49-24947G>A		intron	N/A	NP_001138439.1
	NEDD4L	NM_015277.6		c.49-24947G>A		intron	N/A	NP_056092.2
	NEDD4L	NM_001243960.2		c.49-24947G>A		intron	N/A	NP_001230889.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.49-24947G>A		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000382850.8	TSL:1	c.49-24947G>A		intron	N/A	ENSP00000372301.3
	NEDD4L	ENST00000356462.10	TSL:1	c.49-24947G>A		intron	N/A	ENSP00000348847.5

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55359 AN: 152014 Hom.: 10747 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.409

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

GnomAD4 genome AF: 0.364 AC: 55382 AN: 152132 Hom.: 10745 Cov.: 33 AF XY: 0.358 AC XY: 26620 AN XY: 74376

African (AFR) AF: 0.237 AC: 9838 AN: 41488

American (AMR) AF: 0.359 AC: 5495 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1511 AN: 3470

East Asian (EAS) AF: 0.390 AC: 2018 AN: 5176

South Asian (SAS) AF: 0.433 AC: 2091 AN: 4824

European-Finnish (FIN) AF: 0.274 AC: 2901 AN: 10574

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30192 AN: 67994

Other (OTH) AF: 0.406 AC: 857 AN: 2110

Alfa AF: 0.429 Hom.: 40874

Bravo AF: 0.361

Asia WGS AF: 0.405 AC: 1407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.78
PhyloP100		0.71
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: rs520210; hg19: chr18-55808073;