chr15-55834252-T-C

Variant names:

• chr15-55834252-T-C
• rs140499972
• NM_006154.4:c.2297A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006154.4(NEDD4):​c.2297A>G​(p.Lys766Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00639 in 1,609,900 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (40 hom.)
• Consequence: NEDD4 NM_006154.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.16
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012114316).
• BP6: Variant 15-55834252-T-C is Benign according to our data. Variant chr15-55834252-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 771911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.2297A>G	p.Lys766Arg	missense	Exon 25 of 29	NP_006145.2	P46934-4
	NEDD4	NM_001284338.2		c.3554A>G	p.Lys1185Arg	missense	Exon 21 of 25	NP_001271267.1	P46934-1
	NEDD4	NM_001284339.1		c.3506A>G	p.Lys1169Arg	missense	Exon 21 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.2297A>G	p.Lys766Arg	missense	Exon 25 of 29	ENSP00000410613.3	P46934-4
	NEDD4	ENST00000508342.5	TSL:1	c.3554A>G	p.Lys1185Arg	missense	Exon 21 of 25	ENSP00000424827.1	P46934-1
	NEDD4	ENST00000506154.1	TSL:1	c.3506A>G	p.Lys1169Arg	missense	Exon 21 of 25	ENSP00000422705.1	P46934-2

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 638 AN: 152234 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00704

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00444 AC: 1112 AN: 250254 AF XY: 0.00457

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00312

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00662 AC: 9656 AN: 1457548 Hom.: 40 Cov.: 29 AF XY: 0.00653 AC XY: 4738 AN XY: 725406

African (AFR) AF: 0.000959 AC: 32 AN: 33360

American (AMR) AF: 0.00193 AC: 86 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00793 AC: 207 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00277 AC: 239 AN: 86170

European-Finnish (FIN) AF: 0.00304 AC: 162 AN: 53296

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00777 AC: 8615 AN: 1108278

Other (OTH) AF: 0.00514 AC: 310 AN: 60278

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152352 Hom.: 3 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74506

African (AFR) AF: 0.00147 AC: 61 AN: 41592

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00704 AC: 479 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00648 Hom.: 12

Bravo AF: 0.00407

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.00769 AC: 66

ExAC AF: 0.00430 AC: 522

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00742

EpiControl AF: 0.00707

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.25	N
PhyloP100		6.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Benign	0.052	T
Sift4G	Benign	0.32	T
Polyphen		0.13	B
Vest4		0.70
MVP		0.58
MPC		0.30
ClinPred		0.016	T
GERP RS		5.5
Varity_R		0.58
gMVP		0.35
Mutation Taster		=27/73	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: rs140499972; hg19: chr15-56126450;