18-58044386-T-G

Position:

• chr18-58044386-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144967.3(NEDD4L):​c.-275T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 210,524 control chromosomes in the GnomAD database, including 89,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65362 hom., cov: 32)
  • Exomes 𝑓: 0.90 (24195 hom.)
• Consequence: NEDD4L NM_001144967.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.446

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-58044386-T-G is Benign according to our data. Variant chr18-58044386-T-G is described in ClinVar as [Benign]. Clinvar id is 1251004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.-275T>G		5_prime_UTR_variant	1/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.-275T>G		5_prime_UTR_variant	1/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.931 AC: 139955 AN: 150330 Hom.: 65302 Cov.: 32

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.926

GnomAD4 exome AF: 0.896 AC: 53853 AN: 60086 Hom.: 24195 Cov.: 3 AF XY: 0.893 AC XY: 28044 AN XY: 31400

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.936

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.970

Gnomad4 FIN exome AF: 0.921

Gnomad4 NFE exome AF: 0.877

Gnomad4 OTH exome AF: 0.902

GnomAD4 genome AF: 0.931 AC: 140070 AN: 150438 Hom.: 65362 Cov.: 32 AF XY: 0.936 AC XY: 68756 AN XY: 73496

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.935

Gnomad4 ASJ AF: 0.905

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.981

Gnomad4 FIN AF: 0.931

Gnomad4 NFE AF: 0.893

Gnomad4 OTH AF: 0.927

Alfa AF: 0.891 Hom.: 2878

Bravo AF: 0.934

Asia WGS AF: 0.978 AC: 2996 AN: 3064

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs4496245; hg19: chr18-55711618;