Variant rs3743044 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.1328A>G	p.Asp443Gly	missense_variant	11/20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.1328A>G	p.Asp443Gly	missense_variant	11/20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.1097A>G	p.Asp366Gly	missense_variant	9/17		NP_001269978.1	P40818-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9 link	c.1328A>G	p.Asp443Gly	missense_variant	11/20	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

GnomAD3 exomes

AF:

0.0354

AC:

8883

AN:

251158

Hom.:

230

AF XY:

0.0364

AC XY:

4936

AN XY:

135762

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 SAS exome

AF:

0.0677

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

Gnomad4 AFR exome

AF:

0.0161

Gnomad4 AMR exome

AF:

0.0244

Gnomad4 ASJ exome

AF:

0.0186

Gnomad4 EAS exome

AF:

0.131

Gnomad4 SAS exome

AF:

0.0636

Gnomad4 FIN exome

AF:

0.0330

Gnomad4 NFE exome

AF:

0.0280

Gnomad4 OTH exome

AF:

0.0344

GnomAD4 genome

AF:

0.0295

AC:

4494

AN:

152276

Hom.:

Cov.:

AF XY:

0.0311

AC XY:

2315

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0191

Gnomad4 AMR

AF:

0.0234

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.0958

Gnomad4 SAS

AF:

0.0750

Gnomad4 FIN

AF:

0.0351

Gnomad4 NFE

AF:

0.0290

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0294

Hom.:

207

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.

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

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

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