rs1573390

Variant names:

• chr18-58061220-T-C
• rs1573390
• NM_001144967.3:c.48+16512T>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+16512T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,150 control chromosomes in the GnomAD database, including 50,306 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 0.81 (50306 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.13
• Publications: 5 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 (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.48+16512T>C		intron_variant	Intron 1 of 30	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.48+16512T>C		intron_variant	Intron 1 of 30	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122933 AN: 152032 Hom.: 50266 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.830

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

GnomAD4 genome AF: 0.809 AC: 123028 AN: 152150 Hom.: 50306 Cov.: 32 AF XY: 0.816 AC XY: 60725 AN XY: 74394

African (AFR) AF: 0.678 AC: 28114 AN: 41462

American (AMR) AF: 0.869 AC: 13280 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 3016 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5168 AN: 5180

South Asian (SAS) AF: 0.943 AC: 4549 AN: 4822

European-Finnish (FIN) AF: 0.875 AC: 9274 AN: 10598

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.836 AC: 56841 AN: 68010

Other (OTH) AF: 0.832 AC: 1758 AN: 2112

Alfa AF: 0.832 Hom.: 27423

Bravo AF: 0.803

Asia WGS AF: 0.947 AC: 3294 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	0.12
DANN	Benign	0.19
PhyloP100		-2.1
PromoterAI		-0.0072	Neutral
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: rs1573390; hg19: chr18-55728452;