15-50471748-T-A

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.802T>A(p.Leu268Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,614,050 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L268V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 25 hom., cov: 32)

Exomes 𝑓: 0.022 ( 408 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.84

Publications

15 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=0.0067777038).

BP6

Variant 15-50471748-T-A is Benign according to our data. Variant chr15-50471748-T-A is described in ClinVar as [Benign]. Clinvar id is 458317.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 = 0.0164 (2492/152274) while in subpopulation NFE AF = 0.0252 (1717/68010). AF 95% confidence interval is 0.0243. There are 25 homozygotes in GnomAd4. There are 1154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.802T>A	p.Leu268Ile	missense_variant	Exon 8 of 20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.802T>A	p.Leu268Ile	missense_variant	Exon 8 of 20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.571T>A	p.Leu191Ile	missense_variant	Exon 6 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.802T>A	p.Leu268Ile	missense_variant	Exon 8 of 20	1	NM_005154.5	ENSP00000302239.4		P40818-1

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2491

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0225

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00913

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0253

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0160

AC:

4011

AN:

251216

AF XY:

0.0167

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0216

AC:

31566

AN:

1461776

Hom.:

408

Cov.:

AF XY:

0.0212

AC XY:

15406

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00373

AC:

125

AN:

33478

American (AMR)

AF:

0.0138

AC:

619

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

622

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00929

AC:

801

AN:

86248

European-Finnish (FIN)

AF:

0.00406

AC:

217

AN:

53416

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0251

AC:

27866

AN:

1111958

Other (OTH)

AF:

0.0204

AC:

1232

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1673

3345

5018

6690

8363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1034

2068

3102

4136

5170

<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:

0.0164

AC:

2492

AN:

152274

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1154

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00505

AC:

210

AN:

41570

American (AMR)

AF:

0.0225

AC:

344

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00935

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00368

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0252

AC:

1717

AN:

68010

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

231

347

462

578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0224

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00569

AC:

ESP6500EA

AF:

0.0255

AC:

219

ExAC

AF:

0.0156

AC:

1894

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0285

EpiControl

AF:

0.0289

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 02, 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

0.11

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

.;D;D

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;M;.

PhyloP100

2.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.56

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.065

T;T;D

Sift4G

Benign

0.25

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.35

ClinPred

0.025

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.34

Mutation Taster

=80/20

polymorphism (auto)

(source)

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

Publications

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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