chr15-55860531-T-C

Variant names:

• chr15-55860531-T-C
• rs2303579
• NM_006154.4:c.836A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006154.4(NEDD4):​c.836A>G​(p.Asn279Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,613,736 control chromosomes in the GnomAD database, including 483,395 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. N279K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.72 (40011 hom., cov: 31)
  • Exomes 𝑓: 0.78 (443384 hom.)
• Consequence: NEDD4 NM_006154.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167
• Publications: 44 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3675793E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEDD4	NM_006154.4	c.836A>G	p.Asn279Ser	missense_variant	Exon 11 of 29	ENST00000435532.8	NP_006145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEDD4	ENST00000435532.8	c.836A>G	p.Asn279Ser	missense_variant	Exon 11 of 29	1	NM_006154.4	ENSP00000410613.3

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109511 AN: 151914 Hom.: 40001 Cov.: 31

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.698

GnomAD2 exomes AF: 0.738 AC: 185521 AN: 251344 AF XY: 0.746

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.793

Gnomad EAS exome AF: 0.585

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.796

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.777 AC: 1135749 AN: 1461704 Hom.: 443384 Cov.: 53 AF XY: 0.778 AC XY: 565402 AN XY: 727142

African (AFR) AF: 0.604 AC: 20206 AN: 33470

American (AMR) AF: 0.665 AC: 29723 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 20703 AN: 26132

East Asian (EAS) AF: 0.601 AC: 23840 AN: 39694

South Asian (SAS) AF: 0.758 AC: 65354 AN: 86254

European-Finnish (FIN) AF: 0.720 AC: 38470 AN: 53414

Middle Eastern (MID) AF: 0.720 AC: 4149 AN: 5766

European-Non Finnish (NFE) AF: 0.799 AC: 888037 AN: 1111876

Other (OTH) AF: 0.750 AC: 45267 AN: 60386

GnomAD4 genome AF: 0.721 AC: 109576 AN: 152032 Hom.: 40011 Cov.: 31 AF XY: 0.718 AC XY: 53325 AN XY: 74310

African (AFR) AF: 0.613 AC: 25404 AN: 41454

American (AMR) AF: 0.687 AC: 10498 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2783 AN: 3472

East Asian (EAS) AF: 0.598 AC: 3090 AN: 5166

South Asian (SAS) AF: 0.757 AC: 3644 AN: 4814

European-Finnish (FIN) AF: 0.713 AC: 7523 AN: 10554

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.797 AC: 54184 AN: 67984

Other (OTH) AF: 0.697 AC: 1472 AN: 2112

Alfa AF: 0.768 Hom.: 149113

Bravo AF: 0.709

TwinsUK AF: 0.811 AC: 3007

ALSPAC AF: 0.796 AC: 3067

ESP6500AA AF: 0.613 AC: 2690

ESP6500EA AF: 0.795 AC: 6828

ExAC AF: 0.741 AC: 90007

Asia WGS AF: 0.671 AC: 2337 AN: 3478

EpiCase AF: 0.797

EpiControl AF: 0.781

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.38
DANN	Benign	0.33
DEOGEN2	Benign	0.10	.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.077	T;T;T;T
MetaRNN	Benign	6.4e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.38	.;N;.;.
PhyloP100		-0.17
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.45	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.012
MPC		0.040
ClinPred		0.0085	T
GERP RS		-7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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: rs2303579; hg19: chr15-56152729; COSMIC: COSV59058665; COSMIC: COSV59058665;