ENST00000456173.6:c.-360G>A

Variant names:

• chr18-58195615-G-A
• rs1008899
• ENST00000456173.6:c.-360G>A

Variant summary

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

The ENST00000456173.6(NEDD4L):​c.-360G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,345,426 control chromosomes in the GnomAD database, including 46,323 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 0.22 (4346 hom., cov: 32)
  • Exomes 𝑓: 0.26 (41977 hom.)
• Consequence: NEDD4L ENST00000456173.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• Publications: 19 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

ENSG00000267743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.122+29754G>A		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.122+29754G>A		intron_variant	Intron 2 of 30	1	NM_001144967.3	ENSP00000383199.2

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33810 AN: 151980 Hom.: 4332 Cov.: 32

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.263

GnomAD2 exomes AF: 0.283 AC: 62108 AN: 219548 AF XY: 0.284

Gnomad AFR exome AF: 0.0939

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.463

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.261 AC: 311941 AN: 1193328 Hom.: 41977 Cov.: 33 AF XY: 0.264 AC XY: 156185 AN XY: 590878

African (AFR) AF: 0.0900 AC: 2359 AN: 26200

American (AMR) AF: 0.324 AC: 11738 AN: 36232

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 5501 AN: 16768

East Asian (EAS) AF: 0.453 AC: 7521 AN: 16592

South Asian (SAS) AF: 0.312 AC: 25520 AN: 81910

European-Finnish (FIN) AF: 0.220 AC: 3712 AN: 16840

Middle Eastern (MID) AF: 0.344 AC: 1535 AN: 4458

European-Non Finnish (NFE) AF: 0.255 AC: 242364 AN: 950620

Other (OTH) AF: 0.267 AC: 11691 AN: 43708

GnomAD4 genome AF: 0.222 AC: 33841 AN: 152098 Hom.: 4346 Cov.: 32 AF XY: 0.223 AC XY: 16578 AN XY: 74366

African (AFR) AF: 0.0964 AC: 4003 AN: 41504

American (AMR) AF: 0.266 AC: 4062 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3470

East Asian (EAS) AF: 0.462 AC: 2372 AN: 5136

South Asian (SAS) AF: 0.303 AC: 1462 AN: 4822

European-Finnish (FIN) AF: 0.219 AC: 2323 AN: 10586

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17617 AN: 67984

Other (OTH) AF: 0.267 AC: 563 AN: 2110

Alfa AF: 0.252 Hom.: 16512

Bravo AF: 0.224

Asia WGS AF: 0.357 AC: 1240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-0.47
PromoterAI		0.013	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: rs1008899; hg19: chr18-55862847; COSMIC: COSV56845332; COSMIC: COSV56845332;