9-129868400-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001110303.4(USP20):c.1086G>A(p.Ala362=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,612,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: USP20 NM_001110303.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-129868400-G-A is Benign according to our data. Variant chr9-129868400-G-A is described in ClinVar as [Benign]. Clinvar id is 722847.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.34 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP20	NM_001110303.4	c.1086G>A	p.Ala362=	synonymous_variant	11/26	ENST00000372429.8
USP20	NM_001008563.5	c.1086G>A	p.Ala362=	synonymous_variant	11/26
USP20	NM_006676.8	c.1086G>A	p.Ala362=	synonymous_variant	11/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP20	ENST00000372429.8	c.1086G>A	p.Ala362=	synonymous_variant	11/26	1	NM_001110303.4	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000466 AC: 114 AN: 244566 Hom.: 0 AF XY: 0.000456 AC XY: 61 AN XY: 133764

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000820

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1460214 Hom.: 1 Cov.: 84 AF XY: 0.000173 AC XY: 126 AN XY: 726424

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.00143 AC: 217 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74416

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.00146

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.28
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs200928022; hg19: chr9-132630679;