rs512099

Variant names:

• chr18-58128734-C-T
• rs512099
• NM_001144967.3:c.49-37054C>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.49-37054C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 152,222 control chromosomes in the GnomAD database, including 1,132 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 0.12 (1132 hom., cov: 33)
• Consequence: NEDD4L NM_001144967.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.303
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.218 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	NM_001144967.3	MANE Select	c.49-37054C>T		intron	N/A	NP_001138439.1
	NEDD4L	NM_015277.6		c.49-37054C>T		intron	N/A	NP_056092.2
	NEDD4L	NM_001243960.2		c.49-37054C>T		intron	N/A	NP_001230889.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.49-37054C>T		intron	N/A	ENSP00000383199.2
	NEDD4L	ENST00000382850.8	TSL:1	c.49-37054C>T		intron	N/A	ENSP00000372301.3
	NEDD4L	ENST00000356462.10	TSL:1	c.49-37054C>T		intron	N/A	ENSP00000348847.5

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18194 AN: 152104 Hom.: 1130 Cov.: 33

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0992

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.120 AC: 18224 AN: 152222 Hom.: 1132 Cov.: 33 AF XY: 0.123 AC XY: 9176 AN XY: 74430

African (AFR) AF: 0.132 AC: 5465 AN: 41526

American (AMR) AF: 0.115 AC: 1767 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 602 AN: 3462

East Asian (EAS) AF: 0.215 AC: 1113 AN: 5182

South Asian (SAS) AF: 0.229 AC: 1103 AN: 4816

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10594

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0992 AC: 6750 AN: 68022

Other (OTH) AF: 0.119 AC: 251 AN: 2116

Alfa AF: 0.116 Hom.: 143

Bravo AF: 0.119

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.71
PhyloP100		-0.30
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: rs512099; hg19: chr18-55795966;