rs1975145

Variant names:

• chr18-58263947-C-T
• rs1975145
• NM_001144967.3:c.297+11893C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001144967.3(NEDD4L):​c.297+11893C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 150,090 control chromosomes in the GnomAD database, including 2,765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2765 hom., cov: 32)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144967.3. 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.297+11893C>T		intron	N/A	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_001437337.1		c.1134+7173C>T		intron	N/A	NP_001424266.1	A0A1B0GVY1
	NEDD4L	NM_001144968.2		c.273+11893C>T		intron	N/A	NP_001138440.1	Q96PU5-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.297+11893C>T		intron	N/A	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000357895.9	TSL:1	c.273+11893C>T		intron	N/A	ENSP00000350569.4	Q96PU5-7
	NEDD4L	ENST00000382850.8	TSL:1	c.297+11893C>T		intron	N/A	ENSP00000372301.3	Q96PU5-5

Frequencies

GnomAD3 genomes AF: 0.178 AC: 26757 AN: 149970 Hom.: 2765 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0684

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 26758 AN: 150090 Hom.: 2765 Cov.: 32 AF XY: 0.176 AC XY: 12968 AN XY: 73508

African (AFR) AF: 0.155 AC: 6400 AN: 41322

American (AMR) AF: 0.152 AC: 2307 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3468

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5192

South Asian (SAS) AF: 0.0683 AC: 328 AN: 4804

European-Finnish (FIN) AF: 0.233 AC: 2430 AN: 10416

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14227 AN: 66398

Other (OTH) AF: 0.167 AC: 351 AN: 2106

Alfa AF: 0.189 Hom.: 7727

Bravo AF: 0.169

Asia WGS AF: 0.0500 AC: 172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.22
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1975145; hg19: chr18-55931179;