rs12964776

Positions:

• chr18-58390748-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000400345.8(NEDD4L):​c.2752+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,573,436 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (190 hom.)
• Consequence: NEDD4L ENST00000400345.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001561
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.405

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=-0.59).
• BP6: Variant 18-58390748-C-T is Benign according to our data. Variant chr18-58390748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-58390748-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.011 (1668/152240) while in subpopulation SAS AF= 0.032 (154/4816). AF 95% confidence interval is 0.0279. There are 17 homozygotes in gnomad4. There are 876 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4L	NM_001144967.3	c.2752+6C>T		splice_donor_region_variant, intron_variant		ENST00000400345.8	NP_001138439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2752+6C>T		splice_donor_region_variant, intron_variant		1	NM_001144967.3	ENSP00000383199	P3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1669 AN: 152122 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0322

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0139 AC: 2810 AN: 202232 Hom.: 39 AF XY: 0.0153 AC XY: 1655 AN XY: 107886

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00381

Gnomad ASJ exome AF: 0.00888

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0133 AC: 18966 AN: 1421196 Hom.: 190 Cov.: 26 AF XY: 0.0142 AC XY: 9980 AN XY: 704514

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.00886

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0340

Gnomad4 FIN exome AF: 0.0295

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0110 AC: 1668 AN: 152240 Hom.: 17 Cov.: 32 AF XY: 0.0118 AC XY: 876 AN XY: 74438

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0320

Gnomad4 FIN AF: 0.0286

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0110 Hom.: 7

Bravo AF: 0.00796

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2019	- -

NEDD4L-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Periventricular nodular heterotopia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.030
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: rs12964776; hg19: chr18-56057980;