rs529445

Variant names:

• chr18-58116265-C-A
• rs529445
• NM_001144967.3:c.49-49523C>A

Variant summary

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

The ENST00000400345.8(NEDD4L):​c.49-49523C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,156 control chromosomes in the GnomAD database, including 6,332 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 0.26 (6332 hom., cov: 33)
• Consequence: NEDD4L ENST00000400345.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400345.8. 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.49-49523C>A		intron	N/A	NP_001138439.1
	NEDD4L	NM_015277.6		c.49-49523C>A		intron	N/A	NP_056092.2
	NEDD4L	NM_001243960.2		c.49-49523C>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.49-49523C>A		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000382850.8	TSL:1	c.49-49523C>A		intron	N/A	ENSP00000372301.3
	NEDD4L	ENST00000356462.10	TSL:1	c.49-49523C>A		intron	N/A	ENSP00000348847.5

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39278 AN: 152038 Hom.: 6324 Cov.: 33

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.258 AC: 39319 AN: 152156 Hom.: 6332 Cov.: 33 AF XY: 0.257 AC XY: 19122 AN XY: 74392

African (AFR) AF: 0.453 AC: 18795 AN: 41490

American (AMR) AF: 0.197 AC: 3008 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 903 AN: 3466

East Asian (EAS) AF: 0.0831 AC: 430 AN: 5174

South Asian (SAS) AF: 0.310 AC: 1498 AN: 4826

European-Finnish (FIN) AF: 0.167 AC: 1761 AN: 10572

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12178 AN: 68016

Other (OTH) AF: 0.248 AC: 523 AN: 2112

Alfa AF: 0.211 Hom.: 7211

Bravo AF: 0.267

Asia WGS AF: 0.193 AC: 672 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		-0.021
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: rs529445; hg19: chr18-55783497;