rs535741597

chr15-50494282-T-TAAGA

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.79

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]

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]

ACMG classification

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 GnomAd at 424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP8	NM_005154.5	c.2658+5_2658+8dup		splice_region_variant, intron_variant		ENST00000307179.9
USP8	NM_001128610.3	c.2658+5_2658+8dup		splice_region_variant, intron_variant
USP8	NM_001283049.2	c.2340+5_2340+8dup		splice_region_variant, intron_variant
USP50	XR_007064444.1	n.1918-348_1918-347insTCTT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP8	ENST00000307179.9	c.2658+5_2658+8dup		splice_region_variant, intron_variant		1	NM_005154.5	P1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152220 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00289 AC XY: 356 AN XY: 123158

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.: 8 Cov.: 30 AF XY: 0.00259 AC XY: 1856 AN XY: 716126

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.: 0 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74502

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.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs535741597; hg19: chr15-50786479;