NM_001144967.3:c.49-22287A>G

Variant names:

• chr18-58143501-A-G
• rs549476
• NM_001144967.3:c.49-22287A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001144967.3(NEDD4L):​c.49-22287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 152,134 control chromosomes in the GnomAD database, including 14,278 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 0.43 (14278 hom., cov: 33)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 10 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 (AFR) allele frequency at 95% confidence interval = 0.457 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.49-22287A>G		intron	N/A	NP_001138439.1
	NEDD4L	NM_015277.6		c.49-22287A>G		intron	N/A	NP_056092.2
	NEDD4L	NM_001243960.2		c.49-22287A>G		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.49-22287A>G		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000382850.8	TSL:1	c.49-22287A>G		intron	N/A	ENSP00000372301.3
	NEDD4L	ENST00000356462.10	TSL:1	c.49-22287A>G		intron	N/A	ENSP00000348847.5

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64979 AN: 152016 Hom.: 14263 Cov.: 33

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.427 AC: 65029 AN: 152134 Hom.: 14278 Cov.: 33 AF XY: 0.420 AC XY: 31244 AN XY: 74384

African (AFR) AF: 0.462 AC: 19178 AN: 41476

American (AMR) AF: 0.377 AC: 5761 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1100 AN: 5182

South Asian (SAS) AF: 0.305 AC: 1470 AN: 4822

European-Finnish (FIN) AF: 0.357 AC: 3788 AN: 10596

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.452 AC: 30708 AN: 67982

Other (OTH) AF: 0.436 AC: 919 AN: 2110

Alfa AF: 0.438 Hom.: 27285

Bravo AF: 0.430

Asia WGS AF: 0.253 AC: 882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.086
DANN	Benign	0.20
PhyloP100		-2.1
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: rs549476; hg19: chr18-55810733;