rs116251315

chr18-58391483-C-T

Variant summary

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

The NM_001144967.3(NEDD4L):c.2753-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000922 in 1,570,826 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: NEDD4L NM_001144967.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008782
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.21

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=-0.63).
• BP6: Variant 18-58391483-C-T is Benign according to our data. Variant chr18-58391483-C-T is described in ClinVar as [Benign]. Clinvar id is 417012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (804/152336) while in subpopulation AFR AF= 0.0186 (772/41574). AF 95% confidence interval is 0.0175. There are 7 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 802 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEDD4L	NM_001144967.3	c.2753-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000400345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEDD4L	ENST00000400345.8	c.2753-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001144967.3	P3

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152218 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00106 AC: 199 AN: 188290 Hom.: 0 AF XY: 0.000937 AC XY: 94 AN XY: 100338

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000635

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.000455 AC: 645 AN: 1418490 Hom.: 5 Cov.: 29 AF XY: 0.000373 AC XY: 262 AN XY: 701676

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.000723

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000497

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000460

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152336 Hom.: 7 Cov.: 33 AF XY: 0.00536 AC XY: 399 AN XY: 74484

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00343 Hom.: 1

Bravo AF: 0.00618

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Periventricular nodular heterotopia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	7.0
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0080
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: rs116251315; hg19: chr18-56058715;