chr15-50481590-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005154.5(USP8):c.1328A>G(p.Asp443Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,614,032 control chromosomes in the GnomAD database, including 1,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 91 hom., cov: 33)

Exomes 𝑓: 0.033 ( 1225 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.38

Publications

23 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 Gene-Disease associations (from GenCC):

autosomal recessive spastic paraplegia type 59
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary spastic paraplegia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

USP8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069358647).

BP6

Variant 15-50481590-A-G is Benign according to our data. Variant chr15-50481590-A-G is described in ClinVar as Benign. ClinVar VariationId is 458312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.1328A>G	p.Asp443Gly	missense_variant	Exon 11 of 20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.1328A>G	p.Asp443Gly	missense_variant	Exon 11 of 20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.1097A>G	p.Asp366Gly	missense_variant	Exon 9 of 17		NP_001269978.1	P40818-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9 link	c.1328A>G	p.Asp443Gly	missense_variant	Exon 11 of 20	1	NM_005154.5	ENSP00000302239.4		P40818-1

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4487

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.0959

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0354

AC:

8883

AN:

251158

AF XY:

0.0364

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0169

Gnomad EAS exome

AF:

0.0736

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0328

AC:

47938

AN:

1461756

Hom.:

1225

Cov.:

AF XY:

0.0337

AC XY:

24498

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0161

AC:

540

AN:

33468

American (AMR)

AF:

0.0244

AC:

1091

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0186

AC:

486

AN:

26132

East Asian (EAS)

AF:

0.131

AC:

5218

AN:

39682

South Asian (SAS)

AF:

0.0636

AC:

5480

AN:

86226

European-Finnish (FIN)

AF:

0.0330

AC:

1760

AN:

53410

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0280

AC:

31190

AN:

1111966

Other (OTH)

AF:

0.0344

AC:

2076

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2556

5112

7667

10223

12779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1226

2452

3678

4904

6130

<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:

0.0295

AC:

4494

AN:

152276

Hom.:

Cov.:

AF XY:

0.0311

AC XY:

2315

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0191

AC:

793

AN:

41554

American (AMR)

AF:

0.0234

AC:

357

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.0958

AC:

496

AN:

5180

South Asian (SAS)

AF:

0.0750

AC:

362

AN:

4828

European-Finnish (FIN)

AF:

0.0351

AC:

373

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1972

AN:

68022

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0301

Hom.:

434

Bravo

AF:

0.0254

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0314

AC:

121

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.0264

AC:

227

ExAC

AF:

0.0362

AC:

4390

Asia WGS

AF:

0.127

AC:

440

AN:

3478

EpiCase

AF:

0.0274

EpiControl

AF:

0.0294

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

.;T;T

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

7.4

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.61

ClinPred

0.0071

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.27

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over