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GeneBe

15-50497226-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BA1

The NM_005154.5(USP8):c.3033G>A(p.Leu1011=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,602,510 control chromosomes in the GnomAD database, including 1,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 70 hom., cov: 33)
Exomes 𝑓: 0.031 ( 1010 hom. )

Consequence

USP8
NM_005154.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.84
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.22).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-50497226-G-A is Benign according to our data. Variant chr15-50497226-G-A is described in ClinVar as [Benign]. Clinvar id is 458316.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.84 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USP8NM_005154.5 linkuse as main transcriptc.3033G>A p.Leu1011= synonymous_variant 18/20 ENST00000307179.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USP8ENST00000307179.9 linkuse as main transcriptc.3033G>A p.Leu1011= synonymous_variant 18/201 NM_005154.5 P1P40818-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0244
AC:
3711
AN:
152186
Hom.:
72
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00714
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.0213
Gnomad ASJ
AF:
0.0213
Gnomad EAS
AF:
0.0871
Gnomad SAS
AF:
0.0524
Gnomad FIN
AF:
0.0276
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0289
Gnomad OTH
AF:
0.0187
GnomAD3 exomes
AF:
0.0311
AC:
7422
AN:
238920
Hom.:
155
AF XY:
0.0317
AC XY:
4093
AN XY:
129250
show subpopulations
Gnomad AFR exome
AF:
0.00542
Gnomad AMR exome
AF:
0.0249
Gnomad ASJ exome
AF:
0.0171
Gnomad EAS exome
AF:
0.0632
Gnomad SAS exome
AF:
0.0513
Gnomad FIN exome
AF:
0.0277
Gnomad NFE exome
AF:
0.0284
Gnomad OTH exome
AF:
0.0269
GnomAD4 exome
AF:
0.0309
AC:
44746
AN:
1450206
Hom.:
1010
Cov.:
30
AF XY:
0.0314
AC XY:
22666
AN XY:
721240
show subpopulations
Gnomad4 AFR exome
AF:
0.00482
Gnomad4 AMR exome
AF:
0.0244
Gnomad4 ASJ exome
AF:
0.0187
Gnomad4 EAS exome
AF:
0.122
Gnomad4 SAS exome
AF:
0.0470
Gnomad4 FIN exome
AF:
0.0267
Gnomad4 NFE exome
AF:
0.0279
Gnomad4 OTH exome
AF:
0.0309
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0243
AC:
3706
AN:
152304
Hom.:
70
Cov.:
33
AF XY:
0.0254
AC XY:
1895
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00712
Gnomad4 AMR
AF:
0.0215
Gnomad4 ASJ
AF:
0.0213
Gnomad4 EAS
AF:
0.0869
Gnomad4 SAS
AF:
0.0514
Gnomad4 FIN
AF:
0.0276
Gnomad4 NFE
AF:
0.0289
Gnomad4 OTH
AF:
0.0185
Alfa
AF:
0.0251
Hom.:
64
Bravo
AF:
0.0213
Asia WGS
AF:
0.0910
AC:
316
AN:
3478
EpiCase
AF:
0.0272
EpiControl
AF:
0.0294

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.22
Cadd
Benign
8.6
Dann
Benign
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs11857513; hg19: chr15-50789423; COSMIC: COSV56168874; COSMIC: COSV56168874; API