18-58044675-C-T

Variant names:

• chr18-58044675-C-T
• rs2081489841
• NM_001144967.3:c.15C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001144967.3(NEDD4L):​c.15C>T​(p.Leu5Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,452,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NEDD4L NM_001144967.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.41
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 18-58044675-C-T is Benign according to our data. Variant chr18-58044675-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1920939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.41 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.15C>T	p.Leu5Leu	synonymous	Exon 1 of 31	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_015277.6		c.15C>T	p.Leu5Leu	synonymous	Exon 1 of 30	NP_056092.2
	NEDD4L	NM_001243960.2		c.15C>T	p.Leu5Leu	synonymous	Exon 1 of 29	NP_001230889.1	Q96PU5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.15C>T	p.Leu5Leu	synonymous	Exon 1 of 31	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000382850.8	TSL:1	c.15C>T	p.Leu5Leu	synonymous	Exon 1 of 30	ENSP00000372301.3	Q96PU5-5
	NEDD4L	ENST00000356462.10	TSL:1	c.15C>T	p.Leu5Leu	synonymous	Exon 1 of 29	ENSP00000348847.5	Q96PU5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452050 Hom.: 0 Cov.: 31 AF XY: 0.00000692 AC XY: 5 AN XY: 722342

African (AFR) AF: 0.00 AC: 0 AN: 32518

American (AMR) AF: 0.00 AC: 0 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 38676

South Asian (SAS) AF: 0.0000705 AC: 6 AN: 85144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107850

Other (OTH) AF: 0.00 AC: 0 AN: 59970

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.97
PhyloP100		-2.4
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2081489841; hg19: chr18-55711907;