NM_001144967.3:c.123-16439A>C

Variant names:

• chr18-58228988-A-C
• rs292448
• NM_001144967.3:c.123-16439A>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.123-16439A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 152,026 control chromosomes in the GnomAD database, including 18,436 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 0.46 (18436 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0970
• Publications: 6 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.123-16439A>C		intron_variant	Intron 2 of 30	ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.123-16439A>C		intron_variant	Intron 2 of 30	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70419 AN: 151910 Hom.: 18374 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.482

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

GnomAD4 genome AF: 0.464 AC: 70545 AN: 152026 Hom.: 18436 Cov.: 32 AF XY: 0.463 AC XY: 34394 AN XY: 74324

African (AFR) AF: 0.697 AC: 28889 AN: 41466

American (AMR) AF: 0.453 AC: 6924 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3468

East Asian (EAS) AF: 0.740 AC: 3824 AN: 5166

South Asian (SAS) AF: 0.472 AC: 2278 AN: 4826

European-Finnish (FIN) AF: 0.293 AC: 3084 AN: 10530

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22690 AN: 67978

Other (OTH) AF: 0.486 AC: 1027 AN: 2112

Alfa AF: 0.386 Hom.: 33188

Bravo AF: 0.494

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.8
DANN	Benign	0.48
PhyloP100		-0.097
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: rs292448; hg19: chr18-55896220;