rs292449

Variant names:

• chr18-58227849-G-C
• rs292449
• ENST00000435432.6:c.-300G>C

Variant summary

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

The NM_001144971.2(NEDD4L):​c.-300G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 971,740 control chromosomes in the GnomAD database, including 62,522 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 0.42 (14345 hom., cov: 32)
  • Exomes 𝑓: 0.34 (48177 hom.)
• Consequence: NEDD4L NM_001144971.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.970
• Publications: 23 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144971.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.123-17578G>C		intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001144971.2		c.-300G>C		5_prime_UTR	Exon 3 of 31	NP_001138443.1	Q96PU5-9
	NEDD4L	NM_001144968.2		c.99-17578G>C		intron	N/A	NP_001138440.1	Q96PU5-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000435432.6	TSL:1	c.-300G>C		5_prime_UTR	Exon 3 of 31	ENSP00000393395.1	Q96PU5-9
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.123-17578G>C		intron	N/A	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.99-17578G>C		intron	N/A	ENSP00000350569.4	Q96PU5-7

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63898 AN: 151886 Hom.: 14303 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.337 AC: 276293 AN: 819736 Hom.: 48177 Cov.: 18 AF XY: 0.338 AC XY: 127935 AN XY: 378804

African (AFR) AF: 0.525 AC: 8084 AN: 15404

American (AMR) AF: 0.517 AC: 499 AN: 966

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1975 AN: 5078

East Asian (EAS) AF: 0.807 AC: 2860 AN: 3546

South Asian (SAS) AF: 0.427 AC: 6885 AN: 16130

European-Finnish (FIN) AF: 0.276 AC: 75 AN: 272

Middle Eastern (MID) AF: 0.466 AC: 737 AN: 1580

European-Non Finnish (NFE) AF: 0.327 AC: 245115 AN: 749976

Other (OTH) AF: 0.376 AC: 10063 AN: 26784

GnomAD4 genome AF: 0.421 AC: 63996 AN: 152004 Hom.: 14345 Cov.: 32 AF XY: 0.423 AC XY: 31441 AN XY: 74304

African (AFR) AF: 0.514 AC: 21310 AN: 41426

American (AMR) AF: 0.463 AC: 7076 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1345 AN: 3472

East Asian (EAS) AF: 0.812 AC: 4198 AN: 5172

South Asian (SAS) AF: 0.444 AC: 2137 AN: 4814

European-Finnish (FIN) AF: 0.301 AC: 3177 AN: 10558

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23291 AN: 67968

Other (OTH) AF: 0.455 AC: 960 AN: 2108

Alfa AF: 0.381 Hom.: 1421

Bravo AF: 0.444

Asia WGS AF: 0.606 AC: 2108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.7
DANN	Benign	0.80
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs292449; hg19: chr18-55895081;