9-129868092-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001110303.4(USP20):​c.778G>T​(p.Ala260Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,160 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

USP20
NM_001110303.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.189
Variant links:
Genes affected
USP20 (HGNC:12619): (ubiquitin specific peptidase 20) This gene encodes a ubiquitin specific processing protease that was first identified as a substrate of the VHL (von Hippel-Lindau disease) protein E3 ubiquitin ligase complex. In addition to being ubiquitinated by the VHL-E3 ligase complex, this enzyme deubiquitinates hypoxia-inducible factor (HIF)-1 alpha and thereby causes increased expression of HIF-1alpha targeted genes which play a role in angiogenesis, glucose metabolism, cell proliferation and metastasis. The enzyme encoded by this gene also regulates G-protein coupled receptor signaling by mediating the deubiquitination of beta-2 adrenergic receptor (ADRB2). This enzyme is a ubiquitously expressed thiolester hydrolase. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jan 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03503421).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USP20NM_001110303.4 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 26 ENST00000372429.8 NP_001103773.2 Q9Y2K6
USP20NM_001008563.5 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 26 NP_001008563.2 Q9Y2K6
USP20NM_006676.8 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 25 NP_006667.3 Q9Y2K6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USP20ENST00000372429.8 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 26 1 NM_001110303.4 ENSP00000361506.3 Q9Y2K6
USP20ENST00000315480.9 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 25 1 ENSP00000313811.4 Q9Y2K6
USP20ENST00000358355.5 linkc.778G>T p.Ala260Ser missense_variant Exon 11 of 26 1 ENSP00000351122.1 Q9Y2K6
USP20ENST00000474895.6 linkn.-230G>T upstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
249520
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135392
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000278
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461822
Hom.:
0
Cov.:
89
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000825
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.778G>T (p.A260S) alteration is located in exon 11 (coding exon 9) of the USP20 gene. This alteration results from a G to T substitution at nucleotide position 778, causing the alanine (A) at amino acid position 260 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
4.6
DANN
Benign
0.44
DEOGEN2
Benign
0.015
T;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.68
.;.;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.035
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-0.47
N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.57
N;N;N
REVEL
Benign
0.027
Sift
Benign
0.65
T;T;T
Sift4G
Benign
0.79
T;T;T
Polyphen
0.042
B;B;B
Vest4
0.19
MutPred
0.33
Gain of phosphorylation at A260 (P = 0.0064);Gain of phosphorylation at A260 (P = 0.0064);Gain of phosphorylation at A260 (P = 0.0064);
MVP
0.23
MPC
0.29
ClinPred
0.035
T
GERP RS
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.035
gMVP
0.20

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: rs573247485; hg19: chr9-132630371; API