18-58191171-C-T

Variant names:

• chr18-58191171-C-T
• rs8083578
• NM_001144967.3:c.122+25310C>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.122+25310C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,022 control chromosomes in the GnomAD database, including 10,595 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 0.35 (10595 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267743 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.122+25310C>T		intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001144968.2		c.98+25310C>T		intron	N/A	NP_001138440.1	Q96PU5-7
	NEDD4L	NM_015277.6		c.122+25310C>T		intron	N/A	NP_056092.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.122+25310C>T		intron	N/A	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.98+25310C>T		intron	N/A	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000382850.8	TSL:1	c.122+25310C>T		intron	N/A	ENSP00000372301.3	Q96PU5-5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52361 AN: 151904 Hom.: 10555 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.345 AC: 52462 AN: 152022 Hom.: 10595 Cov.: 32 AF XY: 0.340 AC XY: 25299 AN XY: 74316

African (AFR) AF: 0.570 AC: 23613 AN: 41412

American (AMR) AF: 0.252 AC: 3856 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3466

East Asian (EAS) AF: 0.384 AC: 1991 AN: 5182

South Asian (SAS) AF: 0.304 AC: 1465 AN: 4814

European-Finnish (FIN) AF: 0.213 AC: 2246 AN: 10568

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17221 AN: 67976

Other (OTH) AF: 0.334 AC: 707 AN: 2114

Alfa AF: 0.220 Hom.: 671

Bravo AF: 0.358

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.15
DANN	Benign	0.16
PhyloP100		-1.1
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: rs8083578; hg19: chr18-55858403;