NM_006154.4:c.2496G>A

Variant names:

• chr15-55833039-C-T
• rs201668319
• NM_006154.4:c.2496G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_006154.4(NEDD4):​c.2496G>A​(p.Arg832Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,612,552 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NEDD4 NM_006154.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.061).
• BP6: Variant 15-55833039-C-T is Benign according to our data. Variant chr15-55833039-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 724027.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.

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.2496G>A	p.Arg832Arg	synonymous	Exon 27 of 29	NP_006145.2	P46934-4
	NEDD4	NM_001284338.2		c.3753G>A	p.Arg1251Arg	synonymous	Exon 23 of 25	NP_001271267.1	P46934-1
	NEDD4	NM_001284339.1		c.3705G>A	p.Arg1235Arg	synonymous	Exon 23 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.2496G>A	p.Arg832Arg	synonymous	Exon 27 of 29	ENSP00000410613.3	P46934-4
	NEDD4	ENST00000508342.5	TSL:1	c.3753G>A	p.Arg1251Arg	synonymous	Exon 23 of 25	ENSP00000424827.1	P46934-1
	NEDD4	ENST00000506154.1	TSL:1	c.3705G>A	p.Arg1235Arg	synonymous	Exon 23 of 25	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151802 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251044 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1460750 Hom.: 0 Cov.: 30 AF XY: 0.000117 AC XY: 85 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000112 AC: 5 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111290

Other (OTH) AF: 0.000315 AC: 19 AN: 60342

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151802 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74090

African (AFR) AF: 0.0000242 AC: 1 AN: 41296

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67984

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000166

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.84
DANN	Benign	0.59
PhyloP100		-2.0

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: rs201668319; hg19: chr15-56125237;