18-58044434-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001144967.3(NEDD4L):c.-227C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00966 in 392,406 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (23 hom.)
• Consequence: NEDD4L NM_001144967.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.669

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 18-58044434-C-T is Benign according to our data. Variant chr18-58044434-C-T is described in ClinVar as [Benign]. Clinvar id is 1259629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.-227C>T		5_prime_UTR_variant	1/31	ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.-227C>T		5_prime_UTR_variant	1/31	1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3121 AN: 151124 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0704

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.000532

Gnomad OTH AF: 0.00673

GnomAD4 exome AF: 0.00271 AC: 654 AN: 241178 Hom.: 23 Cov.: 5 AF XY: 0.00256 AC XY: 311 AN XY: 121332

Gnomad4 AFR exome AF: 0.0807

Gnomad4 AMR exome AF: 0.00712

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000654

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.00673

GnomAD4 genome AF: 0.0207 AC: 3136 AN: 151228 Hom.: 105 Cov.: 32 AF XY: 0.0202 AC XY: 1492 AN XY: 73876

Gnomad4 AFR AF: 0.0706

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000532

Gnomad4 OTH AF: 0.00666

Alfa AF: 0.000429 Hom.: 1

Asia WGS AF: 0.00649 AC: 22 AN: 3406

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Uncertain	0.98
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3

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: rs527834236; hg19: chr18-55711666; COSMIC: COSV56844165; COSMIC: COSV56844165;