chr9-129858536-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001110303.4(USP20):c.268G>A(p.Val90Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
USP20
NM_001110303.4 missense
NM_001110303.4 missense
Scores
4
3
11
Clinical Significance
Conservation
PhyloP100: 9.93
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USP20 | NM_001110303.4 | c.268G>A | p.Val90Ile | missense_variant | 6/26 | ENST00000372429.8 | |
USP20 | NM_001008563.5 | c.268G>A | p.Val90Ile | missense_variant | 6/26 | ||
USP20 | NM_006676.8 | c.268G>A | p.Val90Ile | missense_variant | 6/25 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USP20 | ENST00000372429.8 | c.268G>A | p.Val90Ile | missense_variant | 6/26 | 1 | NM_001110303.4 | P1 | |
USP20 | ENST00000315480.9 | c.268G>A | p.Val90Ile | missense_variant | 6/25 | 1 | P1 | ||
USP20 | ENST00000358355.5 | c.268G>A | p.Val90Ile | missense_variant | 6/26 | 1 | P1 | ||
USP20 | ENST00000494971.2 | n.492G>A | non_coding_transcript_exon_variant | 6/6 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249526Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135374
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461856Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19AN XY: 727224
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2023 | The c.268G>A (p.V90I) alteration is located in exon 6 (coding exon 4) of the USP20 gene. This alteration results from a G to A substitution at nucleotide position 268, causing the valine (V) at amino acid position 90 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
D;D;D
Vest4
MutPred
Loss of catalytic residue at V90 (P = 0.0097);Loss of catalytic residue at V90 (P = 0.0097);Loss of catalytic residue at V90 (P = 0.0097);
MVP
MPC
0.47
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at