15-50439193-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005154.5(USP8):c.104+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,365,970 control chromosomes in the GnomAD database, including 20,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18539 hom.)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0130

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-50439193-C-T is Benign according to our data. Variant chr15-50439193-C-T is described in ClinVar as [Benign]. Clinvar id is 1600612.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP8	NM_005154.5	c.104+16C>T		intron_variant		ENST00000307179.9
USP8	NM_001128610.3	c.104+16C>T		intron_variant
USP8	NM_001283049.2	c.104+16C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP8	ENST00000307179.9	c.104+16C>T		intron_variant		1	NM_005154.5	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22885 AN: 151988 Hom.: 2117 Cov.: 32

Gnomad AFR AF: 0.0973

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0799

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.171 AC: 26317 AN: 154088 Hom.: 2747 AF XY: 0.175 AC XY: 14912 AN XY: 85402

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.00235

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.167 AC: 203041 AN: 1213864 Hom.: 18539 Cov.: 17 AF XY: 0.169 AC XY: 101019 AN XY: 598878

Gnomad4 AFR exome AF: 0.0958

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.000934

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.0890

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.151 AC: 22901 AN: 152106 Hom.: 2121 Cov.: 32 AF XY: 0.149 AC XY: 11063 AN XY: 74364

Gnomad4 AFR AF: 0.0975

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.0799

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.186

Alfa AF: 0.181 Hom.: 2792

Bravo AF: 0.164

Asia WGS AF: 0.0990 AC: 344 AN: 3474

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	14
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs11632708; hg19: chr15-50731390;