rs140800682

Variant names:

• chr15-55834113-C-T
• rs140800682
• NM_006154.4:c.2355G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006154.4(NEDD4):​c.2355G>A​(p.Val785Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,613,596 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (43 hom.)
• Consequence: NEDD4 NM_006154.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.221
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 15-55834113-C-T is Benign according to our data. Variant chr15-55834113-C-T is described in ClinVar as Benign. ClinVar VariationId is 721693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.221 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00215 (3145/1461344) while in subpopulation SAS AF = 0.0165 (1419/86238). AF 95% confidence interval is 0.0157. There are 43 homozygotes in GnomAdExome4. There are 1937 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 43 gene

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.2355G>A	p.Val785Val	synonymous	Exon 26 of 29	NP_006145.2	P46934-4
	NEDD4	NM_001284338.2		c.3612G>A	p.Val1204Val	synonymous	Exon 22 of 25	NP_001271267.1	P46934-1
	NEDD4	NM_001284339.1		c.3564G>A	p.Val1188Val	synonymous	Exon 22 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.2355G>A	p.Val785Val	synonymous	Exon 26 of 29	ENSP00000410613.3	P46934-4
	NEDD4	ENST00000508342.5	TSL:1	c.3612G>A	p.Val1204Val	synonymous	Exon 22 of 25	ENSP00000424827.1	P46934-1
	NEDD4	ENST00000506154.1	TSL:1	c.3564G>A	p.Val1188Val	synonymous	Exon 22 of 25	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00925

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00350 AC: 879 AN: 251080 AF XY: 0.00416

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00786

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00215 AC: 3145 AN: 1461344 Hom.: 43 Cov.: 31 AF XY: 0.00266 AC XY: 1937 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0165 AC: 1419 AN: 86238

European-Finnish (FIN) AF: 0.00849 AC: 450 AN: 53016

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.000972 AC: 1081 AN: 1111938

Other (OTH) AF: 0.00210 AC: 127 AN: 60386

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74442

African (AFR) AF: 0.0000482 AC: 2 AN: 41536

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4824

European-Finnish (FIN) AF: 0.00925 AC: 98 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.000740

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.1
DANN	Benign	0.70
PhyloP100		0.22
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140800682; hg19: chr15-56126311;