15-50498883-T-TTCTA

Variant summary

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

The NM_005154.5(USP8):c.3172-16_3172-13dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00997 in 1,568,244 control chromosomes in the GnomAD database, including 104 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0085 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (95 hom.)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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 15-50498883-T-TTCTA is Benign according to our data. Variant chr15-50498883-T-TTCTA is described in ClinVar as [Benign]. Clinvar id is 1601681.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP8	NM_005154.5	c.3172-16_3172-13dup		intron_variant		ENST00000307179.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP8	ENST00000307179.9	c.3172-16_3172-13dup		intron_variant		1	NM_005154.5	P1

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1298 AN: 152174 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00747 AC: 1638 AN: 219298 Hom.: 5 AF XY: 0.00766 AC XY: 912 AN XY: 119042

Gnomad AFR exome AF: 0.00580

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.000181

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00740

GnomAD4 exome AF: 0.0101 AC: 14340 AN: 1415952 Hom.: 95 Cov.: 31 AF XY: 0.0101 AC XY: 7083 AN XY: 700490

Gnomad4 AFR exome AF: 0.00603

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.0000767

Gnomad4 SAS exome AF: 0.00317

Gnomad4 FIN exome AF: 0.00761

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00962

GnomAD4 genome AF: 0.00852 AC: 1298 AN: 152292 Hom.: 9 Cov.: 32 AF XY: 0.00804 AC XY: 599 AN XY: 74462

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0101 Hom.: 2

Bravo AF: 0.00861

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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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: rs200945863; hg19: chr15-50791080;