chr15-55840475-G-C

Position:

• chr15-55840475-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006154.4(NEDD4):​c.2003C>G​(p.Pro668Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NEDD4 NM_006154.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEDD4	NM_006154.4	c.2003C>G	p.Pro668Arg	missense_variant	21/29	ENST00000435532.8	NP_006145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8	c.2003C>G	p.Pro668Arg	missense_variant	21/29	1	NM_006154.4	ENSP00000410613.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.3044C>G (p.P1015R) alteration is located in exon 14 (coding exon 14) of the NEDD4 gene. This alteration results from a C to G substitution at nucleotide position 3044, causing the proline (P) at amino acid position 1015 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D;D;T;D
Sift4G	Benign	0.076	T;D;D;T
Polyphen		0.78	P;P;P;D
Vest4		0.56
MutPred		0.52		.;Gain of catalytic residue at M1083 (P = 0.0373);.;.;
MVP		0.62
MPC		0.32
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-56132673;