rs4941304

Variant names:

• chr18-58064960-T-C
• rs4941304
• NM_001144967.3:c.48+20252T>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.48+20252T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,022 control chromosomes in the GnomAD database, including 38,374 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 0.70 (38374 hom., cov: 31)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• 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: 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 = 0.848 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.48+20252T>C		intron	N/A	NP_001138439.1
	NEDD4L	NM_015277.6		c.48+20252T>C		intron	N/A	NP_056092.2
	NEDD4L	NM_001243960.2		c.48+20252T>C		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.48+20252T>C		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000382850.8	TSL:1	c.48+20252T>C		intron	N/A	ENSP00000372301.3
	NEDD4L	ENST00000356462.10	TSL:1	c.48+20252T>C		intron	N/A	ENSP00000348847.5

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106811 AN: 151904 Hom.: 38351 Cov.: 31

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.869

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.738

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

GnomAD4 genome AF: 0.703 AC: 106885 AN: 152022 Hom.: 38374 Cov.: 31 AF XY: 0.711 AC XY: 52866 AN XY: 74322

African (AFR) AF: 0.546 AC: 22606 AN: 41434

American (AMR) AF: 0.782 AC: 11931 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2747 AN: 3470

East Asian (EAS) AF: 0.869 AC: 4499 AN: 5178

South Asian (SAS) AF: 0.844 AC: 4067 AN: 4818

European-Finnish (FIN) AF: 0.773 AC: 8174 AN: 10568

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.741 AC: 50389 AN: 67982

Other (OTH) AF: 0.741 AC: 1561 AN: 2108

Alfa AF: 0.739 Hom.: 69765

Bravo AF: 0.700

Asia WGS AF: 0.846 AC: 2945 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	2.3
DANN	Benign	0.23
PhyloP100		0.061
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: rs4941304; hg19: chr18-55732192;