18-58044673-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001144967.3(NEDD4L):c.13C>T(p.Leu5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,604,176 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

NEDD4L
NM_001144967.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.103

Publications

3 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040255338).

BP6

Variant 18-58044673-C-T is Benign according to our data. Variant chr18-58044673-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 695592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 74 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEDD4L	NM_001144967.3	MANE Select	c.13C>T	p.Leu5Phe	missense	Exon 1 of 31	NP_001138439.1	Q96PU5-1
NEDD4L	NM_015277.6		c.13C>T	p.Leu5Phe	missense	Exon 1 of 30	NP_056092.2
NEDD4L	NM_001243960.2		c.13C>T	p.Leu5Phe	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.13C>T	p.Leu5Phe	missense	Exon 1 of 31	ENSP00000383199.2	Q96PU5-1
NEDD4L	ENST00000382850.8	TSL:1	c.13C>T	p.Leu5Phe	missense	Exon 1 of 30	ENSP00000372301.3	Q96PU5-5
NEDD4L	ENST00000356462.10	TSL:1	c.13C>T	p.Leu5Phe	missense	Exon 1 of 29	ENSP00000348847.5	Q96PU5-2

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000883

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000549

AC:

128

AN:

233240

AF XY:

0.000575

show subpopulations

Gnomad AFR exome

AF:

0.000224

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.000417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000937

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.000605

AC:

878

AN:

1452030

Hom.:

Cov.:

AF XY:

0.000608

AC XY:

439

AN XY:

722328

show subpopulations

African (AFR)

AF:

0.000185

AC:

AN:

32490

American (AMR)

AF:

0.000228

AC:

AN:

43944

Ashkenazi Jewish (ASJ)

AF:

0.000348

AC:

AN:

25850

East Asian (EAS)

AF:

0.00

AC:

AN:

38682

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85138

European-Finnish (FIN)

AF:

0.000229

AC:

AN:

52448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.000729

AC:

808

AN:

1107770

Other (OTH)

AF:

0.000534

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000883

AC:

AN:

67950

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.000283

AC:

ESP6500EA

AF:

0.000249

AC:

ExAC

AF:

0.000749

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

NEDD4L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.065

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

-0.10

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.26

REVEL

Benign

0.026

Sift

Benign

0.14

Sift4G

Benign

0.35

Polyphen

0.89

Vest4

0.12

MVP

0.53

MPC

0.45

ClinPred

0.091

GERP RS

3.3

PromoterAI

0.022

Neutral

(source)

Varity_R

0.14

gMVP

0.12

Mutation Taster

=90/10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over