18-58336932-T-C

Variant names:

• chr18-58336932-T-C
• rs3865418
• NM_001144967.3:c.1125+1395T>C

Variant summary

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

The NM_001144967.3(NEDD4L):​c.1125+1395T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,050 control chromosomes in the GnomAD database, including 18,715 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 0.49 (18715 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.461
• Publications: 14 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 (EAS) allele frequency at 95% confidence interval = 0.642 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.1125+1395T>C		intron	N/A	NP_001138439.1
	NEDD4L	NM_001437337.1		c.1962+1395T>C		intron	N/A	NP_001424266.1
	NEDD4L	NM_001144968.2		c.1101+1395T>C		intron	N/A	NP_001138440.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.1125+1395T>C		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000357895.9	TSL:1	c.1101+1395T>C		intron	N/A	ENSP00000350569.4
	NEDD4L	ENST00000382850.8	TSL:1	c.1065+3040T>C		intron	N/A	ENSP00000372301.3

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74627 AN: 151932 Hom.: 18704 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.472

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

GnomAD4 genome AF: 0.491 AC: 74665 AN: 152050 Hom.: 18715 Cov.: 32 AF XY: 0.502 AC XY: 37338 AN XY: 74342

African (AFR) AF: 0.415 AC: 17204 AN: 41456

American (AMR) AF: 0.525 AC: 8025 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1410 AN: 3470

East Asian (EAS) AF: 0.660 AC: 3415 AN: 5174

South Asian (SAS) AF: 0.642 AC: 3095 AN: 4818

European-Finnish (FIN) AF: 0.608 AC: 6426 AN: 10572

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.493 AC: 33474 AN: 67964

Other (OTH) AF: 0.471 AC: 993 AN: 2110

Alfa AF: 0.481 Hom.: 5852

Bravo AF: 0.478

Asia WGS AF: 0.599 AC: 2085 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	6.5
DANN	Benign	0.52
PhyloP100		0.46
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: rs3865418; hg19: chr18-56004164;