ENST00000357895.9:c.24G>A

Variant names:

• chr18-58149559-G-A
• rs4149601
• ENST00000357895.9:c.24G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000357895.9(NEDD4L):​c.24G>A​(p.Gln8Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,541,682 control chromosomes in the GnomAD database, including 82,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8096 hom., cov: 33)
  • Exomes 𝑓: 0.32 (73942 hom.)
• Consequence: NEDD4L ENST00000357895.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001359
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.453
• Publications: 92 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-58149559-G-A is Benign according to our data. Variant chr18-58149559-G-A is described in ClinVar as Benign. ClinVar VariationId is 225996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357895.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.49-16229G>A		intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001144968.2		c.24G>A	p.Gln8Gln	splice_region synonymous	Exon 1 of 31	NP_001138440.1	Q96PU5-7
	NEDD4L	NM_001144969.2		c.24G>A	p.Gln8Gln	splice_region synonymous	Exon 1 of 30	NP_001138441.1	Q96PU5-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000357895.9	TSL:1	c.24G>A	p.Gln8Gln	splice_region synonymous	Exon 1 of 31	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000586263.5	TSL:1	c.24G>A	p.Gln8Gln	splice_region synonymous	Exon 1 of 30	ENSP00000468546.1	Q96PU5-6
	NEDD4L	ENST00000435432.6	TSL:1	c.-404G>A		5_prime_UTR	Exon 1 of 31	ENSP00000393395.1	Q96PU5-9

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48814 AN: 151970 Hom.: 8088 Cov.: 33

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.282 AC: 43330 AN: 153806 AF XY: 0.281

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.321 AC: 446018 AN: 1389594 Hom.: 73942 Cov.: 27 AF XY: 0.318 AC XY: 218055 AN XY: 686008

African (AFR) AF: 0.353 AC: 11084 AN: 31392

American (AMR) AF: 0.184 AC: 6550 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10319 AN: 25100

East Asian (EAS) AF: 0.169 AC: 6045 AN: 35680

South Asian (SAS) AF: 0.197 AC: 15546 AN: 78940

European-Finnish (FIN) AF: 0.311 AC: 15322 AN: 49246

Middle Eastern (MID) AF: 0.344 AC: 1951 AN: 5676

European-Non Finnish (NFE) AF: 0.337 AC: 360966 AN: 1070284

Other (OTH) AF: 0.316 AC: 18235 AN: 57628

GnomAD4 genome AF: 0.321 AC: 48849 AN: 152088 Hom.: 8096 Cov.: 33 AF XY: 0.318 AC XY: 23623 AN XY: 74352

African (AFR) AF: 0.345 AC: 14292 AN: 41466

American (AMR) AF: 0.263 AC: 4015 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1422 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1049 AN: 5182

South Asian (SAS) AF: 0.190 AC: 915 AN: 4818

European-Finnish (FIN) AF: 0.308 AC: 3260 AN: 10576

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22760 AN: 67978

Other (OTH) AF: 0.327 AC: 690 AN: 2108

Alfa AF: 0.327 Hom.: 31050

Bravo AF: 0.320

Asia WGS AF: 0.204 AC: 711 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.87
PhyloP100		0.45
PromoterAI		0.068	Neutral
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.070		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: rs4149601; hg19: chr18-55816791; COSMIC: COSV56843798;