NM_006154.4:c.2534A>G

Variant names:

• chr15-55830580-T-C
• rs149901812
• NM_006154.4:c.2534A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006154.4(NEDD4):​c.2534A>G​(p.Asn845Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NEDD4 NM_006154.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23974329).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4	NM_006154.4	MANE Select	c.2534A>G	p.Asn845Ser	missense	Exon 28 of 29	NP_006145.2	P46934-4
	NEDD4	NM_001284338.2		c.3791A>G	p.Asn1264Ser	missense	Exon 24 of 25	NP_001271267.1	P46934-1
	NEDD4	NM_001284339.1		c.3743A>G	p.Asn1248Ser	missense	Exon 24 of 25	NP_001271268.1	P46934-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEDD4	ENST00000435532.8	TSL:1 MANE Select	c.2534A>G	p.Asn845Ser	missense	Exon 28 of 29	ENSP00000410613.3	P46934-4
	NEDD4	ENST00000508342.5	TSL:1	c.3791A>G	p.Asn1264Ser	missense	Exon 24 of 25	ENSP00000424827.1	P46934-1
	NEDD4	ENST00000506154.1	TSL:1	c.3743A>G	p.Asn1248Ser	missense	Exon 24 of 25	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251416 AF XY: 0.0000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.000133 AC XY: 97 AN XY: 727162

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000195 AC: 217 AN: 1111818

Other (OTH) AF: 0.000348 AC: 21 AN: 60386

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.12
Sift	Benign	0.088	T
Sift4G	Uncertain	0.050	T
Polyphen		0.011	B
Vest4		0.37
MVP		0.55
MPC		0.041
ClinPred		0.32	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.37
Mutation Taster		=34/66	disease causing

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: rs149901812; hg19: chr15-56122778;