Variant rs147742292 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005154.5(USP8):c.583A>G(p.Lys195Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,614,170 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.58

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:

USP8 (HGNC:):

USP8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046359897).

BP6

Variant 15-50465088-A-G is Benign according to our data. Variant chr15-50465088-A-G is described in ClinVar as [Benign]. Clinvar id is 528043.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP8	NM_005154.5 linkuse as main transcript	c.583A>G	p.Lys195Glu	missense_variant	7/20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 linkuse as main transcript	c.583A>G	p.Lys195Glu	missense_variant	7/20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 linkuse as main transcript	c.352A>G	p.Lys118Glu	missense_variant	5/17		NP_001269978.1	P40818-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9 linkuse as main transcript	c.583A>G	p.Lys195Glu	missense_variant	7/20	1	NM_005154.5	ENSP00000302239.4		P40818-1

Frequencies

GnomAD3 genomes

AF:

0.00191

AC:

291

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00203

AC:

511

AN:

251370

Hom.:

AF XY:

0.00205

AC XY:

278

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00187

AC:

2729

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1346

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152348

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0129

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000918

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00203

AC:

247

EpiCase

AF:

0.00147

EpiControl

AF:

0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

T;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.65

.;T;T

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.95

N;N;N

REVEL

Benign

0.073

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.21

MVP

0.22

ClinPred

0.016

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over