rs8094327

Variant names:

• chr18-58295813-A-G
• rs8094327
• NM_001144967.3:c.298-20169A>G

Variant summary

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

The NM_001144967.3(NEDD4L):​c.298-20169A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 151,990 control chromosomes in the GnomAD database, including 2,445 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 0.17 (2445 hom., cov: 31)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.298-20169A>G		intron_variant	Intron 5 of 30	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.298-20169A>G		intron_variant	Intron 5 of 30	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25968 AN: 151870 Hom.: 2437 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.171 AC: 26003 AN: 151990 Hom.: 2445 Cov.: 31 AF XY: 0.176 AC XY: 13065 AN XY: 74304

African (AFR) AF: 0.136 AC: 5625 AN: 41450

American (AMR) AF: 0.149 AC: 2272 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 716 AN: 3470

East Asian (EAS) AF: 0.0558 AC: 289 AN: 5176

South Asian (SAS) AF: 0.0998 AC: 481 AN: 4818

European-Finnish (FIN) AF: 0.306 AC: 3225 AN: 10532

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.188 AC: 12792 AN: 67966

Other (OTH) AF: 0.176 AC: 371 AN: 2110

Alfa AF: 0.171 Hom.: 322

Bravo AF: 0.160

Asia WGS AF: 0.0740 AC: 258 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.1
DANN	Benign	0.69
PhyloP100		-0.12
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: rs8094327; hg19: chr18-55963045;