15-50462296-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005154.5(USP8):ā€‹c.515A>Gā€‹(p.Asn172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,603,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.00012 ( 0 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.025842637).
BS2
High AC in GnomAdExome4 at 171 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP8NM_005154.5 linkuse as main transcriptc.515A>G p.Asn172Ser missense_variant 6/20 ENST00000307179.9 NP_005145.3
USP8NM_001128610.3 linkuse as main transcriptc.515A>G p.Asn172Ser missense_variant 6/20 NP_001122082.1
USP8NM_001283049.2 linkuse as main transcriptc.284A>G p.Asn95Ser missense_variant 4/17 NP_001269978.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP8ENST00000307179.9 linkuse as main transcriptc.515A>G p.Asn172Ser missense_variant 6/201 NM_005154.5 ENSP00000302239 P1P40818-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000667
AC:
16
AN:
239880
Hom.:
0
AF XY:
0.0000540
AC XY:
7
AN XY:
129658
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000126
Gnomad OTH exome
AF:
0.000341
GnomAD4 exome
AF:
0.000118
AC:
171
AN:
1450946
Hom.:
0
Cov.:
31
AF XY:
0.000109
AC XY:
79
AN XY:
721576
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000148
Gnomad4 OTH exome
AF:
0.000117
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000120
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000179

ClinVar

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

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 01, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with USP8-related conditions. This variant is present in population databases (rs147121994, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 172 of the USP8 protein (p.Asn172Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
16
DANN
Benign
0.70
DEOGEN2
Benign
0.024
T;T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.72
.;T;T
M_CAP
Benign
0.0033
T
MetaRNN
Benign
0.026
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.26
N;N;.
MutationTaster
Benign
0.65
D;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.28
N;N;N
REVEL
Benign
0.040
Sift
Benign
0.61
T;T;T
Sift4G
Benign
0.75
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.066
MVP
0.15
ClinPred
0.032
T
GERP RS
-0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.029
gMVP
0.072

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs147121994; hg19: chr15-50754493; API