18-58044682-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001144967.3(NEDD4L):c.22C>T(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. P8L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NEDD4L
NM_001144967.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.196

Publications

0 publications found

Variant links:

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

NEDD4L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.075176775).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEDD4L	NM_001144967.3	MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 31	NP_001138439.1	Q96PU5-1
NEDD4L	NM_015277.6		c.22C>T	p.Pro8Ser	missense	Exon 1 of 30	NP_056092.2
NEDD4L	NM_001243960.2		c.22C>T	p.Pro8Ser	missense	Exon 1 of 29	NP_001230889.1	Q96PU5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEDD4L	ENST00000400345.8	TSL:1 MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 31	ENSP00000383199.2	Q96PU5-1
NEDD4L	ENST00000382850.8	TSL:1	c.22C>T	p.Pro8Ser	missense	Exon 1 of 30	ENSP00000372301.3	Q96PU5-5
NEDD4L	ENST00000356462.10	TSL:1	c.22C>T	p.Pro8Ser	missense	Exon 1 of 29	ENSP00000348847.5	Q96PU5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32544

American (AMR)

AF:

0.0000227

AC:

AN:

43984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

38724

South Asian (SAS)

AF:

0.00

AC:

AN:

85178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108040

Other (OTH)

AF:

0.00

AC:

AN:

60016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.34

PhyloP100

0.20

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.83

REVEL

Benign

0.030

Sift

Benign

0.39

Sift4G

Benign

0.22

Polyphen

0.0050

Vest4

0.17

MutPred

0.15

Gain of phosphorylation at P8 (P = 0.0302)

MVP

0.34

MPC

1.1

ClinPred

0.25

GERP RS

-0.98

PromoterAI

0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.079

gMVP

0.27

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over