Genetic Variant NM_001144967.3:c.48+1_48+363del (chr18-58044706-GAGGTGAGTGGCACCCCCTTCCTGCTCGGGACTCCCCGGGGAGTTCCTATCCCGCGCCGGCAGGGGGAGGGGAAAGGGGCCGTCCCCGGGGTGCTCGTGCCCAGCGTCTGCAGGGGAGCCCCAAAGCGGGAGCGCCCCGGAGCGGGATCCAGGGGAGCTTGGGTCCTTCCGCACCCCCCACCCTCCGCAAGCCGAGCTCATTGTTTGTAAATAAAGCGGCGCGACGCCCTTGGAGCTGGGGGTTCACTCCGCAGCTCCTCGCTTTCGGGAGGAGAGGGAGGGGGCATGCGTGCCTCTCTTCCCTCTTCCTCTCCAAGCAGCGTCTCCCGGGGCTGTTGGGCAACTTTCCGCCTCTCGCCCCTGC-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001144967.3(NEDD4L):c.48+1_48+363del variant causes a splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NEDD4L
NM_001144967.3 splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16495901 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3 link	c.48+1_48+363del		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 30	ENST00000400345.8	NP_001138439.1	Q96PU5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8 link	c.47_48+361del	p.Glu16GlyfsTer840	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 31	1	NM_001144967.3	ENSP00000383199.2		Q96PU5-1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 1 of the NEDD4L gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEDD4L cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEDD4L-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.