rs535741597

Variant names:

• chr15-50494282-T-TAAGA
• rs535741597
• NM_005154.5:c.2658+5_2658+8dupGAAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000307179.9(USP8):​c.2658+2_2658+3insAAGA 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 ENST00000307179.9 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -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 VariationId is 458315.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000307179.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	NM_005154.5	MANE Select	c.2658+5_2658+8dupGAAA		intron	N/A	NP_005145.3
	USP8	NM_001128610.3		c.2658+5_2658+8dupGAAA		intron	N/A	NP_001122082.1
	USP8	NM_001283049.2		c.2340+5_2340+8dupGAAA		intron	N/A	NP_001269978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.2658+2_2658+3insAAGA		splice_region intron	N/A	ENSP00000302239.4
	USP8	ENST00000396444.7	TSL:1	c.2658+2_2658+3insAAGA		splice_region intron	N/A	ENSP00000379721.3
	USP8	ENST00000956759.1		c.2784+2_2784+3insAAGA		splice_region intron	N/A	ENSP00000626818.1

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

GnomAD2 exomes AF: 0.00275 AC: 626 AN: 227292 AF XY: 0.00289

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 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

African (AFR) AF: 0.000530 AC: 17 AN: 32090

American (AMR) AF: 0.00209 AC: 80 AN: 38258

Ashkenazi Jewish (ASJ) AF: 0.00538 AC: 133 AN: 24724

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00167 AC: 138 AN: 82410

European-Finnish (FIN) AF: 0.00250 AC: 132 AN: 52792

Middle Eastern (MID) AF: 0.00698 AC: 36 AN: 5154

European-Non Finnish (NFE) AF: 0.00271 AC: 2993 AN: 1105712

Other (OTH) AF: 0.00286 AC: 170 AN: 59400

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74502

African (AFR) AF: 0.000361 AC: 15 AN: 41578

American (AMR) AF: 0.00235 AC: 36 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00403 AC: 274 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00313 Hom.: 0

Bravo AF: 0.00241

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs535741597; hg19: chr15-50786479; COSMIC: COSV56164198; COSMIC: COSV56164198;