rs768863821

Variant names:

• chr18-58044670-G-A
• rs768863821
• NM_001144967.3:c.10G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-58044670-G-A
• chr18-58044670-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144967.3(NEDD4L):​c.10G>A​(p.Gly4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,642 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEDD4L NM_001144967.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16804641).

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.10G>A	p.Gly4Arg	missense	Exon 1 of 31	NP_001138439.1	Q96PU5-1
	NEDD4L	NM_015277.6		c.10G>A	p.Gly4Arg	missense	Exon 1 of 30	NP_056092.2
	NEDD4L	NM_001243960.2		c.10G>A	p.Gly4Arg	missense	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.10G>A	p.Gly4Arg	missense	Exon 1 of 31	ENSP00000383199.2	Q96PU5-1
	NEDD4L	ENST00000382850.8	TSL:1	c.10G>A	p.Gly4Arg	missense	Exon 1 of 30	ENSP00000372301.3	Q96PU5-5
	NEDD4L	ENST00000356462.10	TSL:1	c.10G>A	p.Gly4Arg	missense	Exon 1 of 29	ENSP00000348847.5	Q96PU5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449642 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721140

African (AFR) AF: 0.00 AC: 0 AN: 32288

American (AMR) AF: 0.00 AC: 0 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.00 AC: 0 AN: 38424

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106652

Other (OTH) AF: 0.00 AC: 0 AN: 59836

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.0070	B
Vest4		0.26
MutPred		0.14		Gain of phosphorylation at T3 (P = 0.1257)
MVP		0.70
MPC		0.50
ClinPred		0.11	T
GERP RS		2.4
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.28
Mutation Taster		=78/22	polymorphism

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: rs768863821; hg19: chr18-55711902;