Variant rs535741597 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_005154.5(USP8):c.2658+5_2658+8dup variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00259 in 1,592,458 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 8 hom. )

Consequence

USP8
NM_005154.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.79

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:

USP50 (HGNC:20079): (ubiquitin specific peptidase 50) Enables ubiquitin-like protein-specific protease activity. Acts upstream of or within several processes, including nuclear speck organization; positive regulation of NLRP3 inflammasome complex assembly; and positive regulation of macromolecule metabolic process. Predicted to be active in several cellular components, including dendritic spine; midbody; and postsynaptic density. Predicted to be extrinsic component of endosome membrane and extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

USP50 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 15-50494282-T-TAAGA is Benign according to our data. Variant chr15-50494282-T-TAAGA is described in ClinVar as [Likely_benign]. Clinvar id is 458315.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 423 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
USP8	NM_005154.5 linkuse as main transcript	c.2658+5_2658+8dup	splice_region_variant, intron_variant	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3 linkuse as main transcript	c.2658+5_2658+8dup	splice_region_variant, intron_variant		NP_001122082.1
USP8	NM_001283049.2 linkuse as main transcript	c.2340+5_2340+8dup	splice_region_variant, intron_variant		NP_001269978.1
USP50	XR_007064444.1 linkuse as main transcript	n.1918-348_1918-347insTCTT	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9 linkuse as main transcript	c.2658+5_2658+8dup		splice_region_variant, intron_variant		1	NM_005154.5	ENSP00000302239	P1	P40818-1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00403

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00275

AC:

626

AN:

227292

Hom.:

AF XY:

0.00289

AC XY:

356

AN XY:

123158

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.00216

Gnomad ASJ exome

AF:

0.00529

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.00293

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00257

AC:

3699

AN:

1440120

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1856

AN XY:

716126

show subpopulations

Gnomad4 AFR exome

AF:

0.000530

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.00538

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00167

Gnomad4 FIN exome

AF:

0.00250

Gnomad4 NFE exome

AF:

0.00271

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00278

AC:

423

AN:

152338

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00452

Gnomad4 NFE

AF:

0.00403

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00241

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

Hereditary spastic paraplegia

Benign:1

Likely 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

Splicing

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