Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005154.5(USP8):c.3033G>A(p.Leu1011Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,602,510 control chromosomes in the GnomAD database, including 1,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 70 hom., cov: 33)

Exomes 𝑓: 0.031 ( 1010 hom. )

Consequence

USP8
NM_005154.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.84

Publications

14 publications found

Variant links:

Genes affected

USP8 (HGNC:12631): (ubiquitin specific peptidase 8) This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USP8 links:

USP50 (HGNC:20079): (ubiquitin specific peptidase 50) Enables ubiquitin-like protein-specific protease activity. Acts upstream of or within several processes, including nuclear speck organization; positive regulation of NLRP3 inflammasome complex assembly; and positive regulation of macromolecule metabolic process. Predicted to be active in several cellular components, including dendritic spine; midbody; and postsynaptic density. Predicted to be extrinsic component of endosome membrane and extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

USP50 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP6

Variant 15-50497226-G-A is Benign according to our data. Variant chr15-50497226-G-A is described in ClinVar as Benign. ClinVar VariationId is 458316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USP8	NM_005154.5	MANE Select	c.3033G>A	p.Leu1011Leu	synonymous	Exon 18 of 20	NP_005145.3
USP8	NM_001128610.3		c.3033G>A	p.Leu1011Leu	synonymous	Exon 18 of 20	NP_001122082.1
USP8	NM_001283049.2		c.2715G>A	p.Leu905Leu	synonymous	Exon 15 of 17	NP_001269978.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USP8	ENST00000307179.9	TSL:1 MANE Select	c.3033G>A	p.Leu1011Leu	synonymous	Exon 18 of 20	ENSP00000302239.4
USP8	ENST00000396444.7	TSL:1	c.3033G>A	p.Leu1011Leu	synonymous	Exon 18 of 20	ENSP00000379721.3
USP8	ENST00000425032.7	TSL:2	c.2715G>A	p.Leu905Leu	synonymous	Exon 15 of 17	ENSP00000412682.3

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3711

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00714

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.0871

Gnomad SAS

AF:

0.0524

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0289

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0311

AC:

7422

AN:

238920

AF XY:

0.0317

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.0632

Gnomad FIN exome

AF:

0.0277

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0269

GnomAD4 exome

AF:

0.0309

AC:

44746

AN:

1450206

Hom.:

1010

Cov.:

AF XY:

0.0314

AC XY:

22666

AN XY:

721240

show subpopulations

African (AFR)

AF:

0.00482

AC:

157

AN:

32556

American (AMR)

AF:

0.0244

AC:

1013

AN:

41442

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

481

AN:

25654

East Asian (EAS)

AF:

0.122

AC:

4812

AN:

39350

South Asian (SAS)

AF:

0.0470

AC:

3927

AN:

83558

European-Finnish (FIN)

AF:

0.0267

AC:

1423

AN:

53268

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0279

AC:

30988

AN:

1108800

Other (OTH)

AF:

0.0309

AC:

1853

AN:

59876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2093

4186

6280

8373

10466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1198

2396

3594

4792

5990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0243

AC:

3706

AN:

152304

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1895

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00712

AC:

296

AN:

41584

American (AMR)

AF:

0.0215

AC:

329

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3468

East Asian (EAS)

AF:

0.0869

AC:

451

AN:

5190

South Asian (SAS)

AF:

0.0514

AC:

248

AN:

4824

European-Finnish (FIN)

AF:

0.0276

AC:

293

AN:

10612

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0289

AC:

1964

AN:

68002

Other (OTH)

AF:

0.0185

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0281

Hom.:

238

Bravo

AF:

0.0213

Asia WGS

AF:

0.0910

AC:

316

AN:

3478

EpiCase

AF:

0.0272

EpiControl

AF:

0.0294

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

8.6

(source)

DANN

Benign

0.89

PhyloP100

1.8

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs11857513

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over