rs61733869

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005154.5(USP8):c.1042G>A(p.Ala348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,613,798 control chromosomes in the GnomAD database, including 1,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 78 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1254 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.114

Publications

10 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=0.001880914).

BP6

Variant 15-50477323-G-A is Benign according to our data. Variant chr15-50477323-G-A is described in ClinVar as Benign. ClinVar VariationId is 458310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.026 (3952/152178) while in subpopulation NFE AF = 0.0416 (2827/68000). AF 95% confidence interval is 0.0403. There are 78 homozygotes in GnomAd4. There are 1787 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 78 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.1042G>A	p.Ala348Thr	missense_variant	Exon 10 of 20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.1042G>A	p.Ala348Thr	missense_variant	Exon 10 of 20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.811G>A	p.Ala271Thr	missense_variant	Exon 8 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.1042G>A	p.Ala348Thr	missense_variant	Exon 10 of 20	1	NM_005154.5	ENSP00000302239.4		P40818-1

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3954

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00833

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0273

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0316

GnomAD2 exomes

AF:

0.0259

AC:

6498

AN:

250846

AF XY:

0.0266

show subpopulations

Gnomad AFR exome

AF:

0.00650

Gnomad AMR exome

AF:

0.0177

Gnomad ASJ exome

AF:

0.0310

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.0414

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0384

AC:

56111

AN:

1461620

Hom.:

1254

Cov.:

AF XY:

0.0375

AC XY:

27287

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00681

AC:

228

AN:

33478

American (AMR)

AF:

0.0194

AC:

868

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0306

AC:

799

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.00707

AC:

610

AN:

86242

European-Finnish (FIN)

AF:

0.0187

AC:

1000

AN:

53412

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0454

AC:

50441

AN:

1111816

Other (OTH)

AF:

0.0349

AC:

2110

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

2762

5525

8287

11050

13812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1882

3764

5646

7528

9410

<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:

0.0260

AC:

3952

AN:

152178

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1787

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00831

AC:

345

AN:

41536

American (AMR)

AF:

0.0272

AC:

416

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

119

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0133

AC:

141

AN:

10578

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2827

AN:

68000

Other (OTH)

AF:

0.0313

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0372

Hom.:

292

Bravo

AF:

0.0270

TwinsUK

AF:

0.0372

AC:

138

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.0105

AC:

ESP6500EA

AF:

0.0434

AC:

373

ExAC

AF:

0.0255

AC:

3090

Asia WGS

AF:

0.00462

AC:

AN:

3476

EpiCase

AF:

0.0426

EpiControl

AF:

0.0424

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Benign:1

Feb 03, 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

Benign

0.066

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.54

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.61

.;T;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N;.

PhyloP100

-0.11

PrimateAI

Benign

0.24

PROVEAN

Benign

0.26

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.59

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.020

ClinPred

0.0012

GERP RS

-9.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.17

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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