dbSNP rs772614059: NEDD4:p.Arg740Leu (chr15-55837832-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006154.4(NEDD4):c.2219G>T(p.Arg740Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R740Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NEDD4
NM_006154.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.02

Publications

0 publications found

Variant links:

Genes affected

NEDD4 (HGNC:7727): (NEDD4 E3 ubiquitin protein ligase) This gene is the founding member of the NEDD4 family of HECT ubiquitin ligases that function in the ubiquitin proteasome system of protein degradation. The encoded protein contains an N-terminal calcium and phospholipid binding C2 domain followed by multiple tryptophan-rich WW domains and, a C-terminal HECT ubiquitin ligase catalytic domain. It plays critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumor suppressor PTEN. [provided by RefSeq, Jul 2016]

NEDD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006154.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEDD4	NM_006154.4	MANE Select	c.2219G>T	p.Arg740Leu	missense	Exon 24 of 29	NP_006145.2	P46934-4
NEDD4	NM_001284338.2		c.3476G>T	p.Arg1159Leu	missense	Exon 20 of 25	NP_001271267.1	P46934-1
NEDD4	NM_001284339.1		c.3428G>T	p.Arg1143Leu	missense	Exon 20 of 25	NP_001271268.1	P46934-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEDD4	ENST00000435532.8	TSL:1 MANE Select	c.2219G>T	p.Arg740Leu	missense	Exon 24 of 29	ENSP00000410613.3	P46934-4
NEDD4	ENST00000508342.5	TSL:1	c.3476G>T	p.Arg1159Leu	missense	Exon 20 of 25	ENSP00000424827.1	P46934-1
NEDD4	ENST00000506154.1	TSL:1	c.3428G>T	p.Arg1143Leu	missense	Exon 20 of 25	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110336

Other (OTH)

AF:

0.0000166

AC:

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PhyloP100

6.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.91

MutPred

0.75

Loss of MoRF binding (P = 0.0083)

MVP

0.70

MPC

0.34

ClinPred

1.0

GERP RS

4.9

Varity_R

0.86

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over