9-129868140-C-G

Variant names:

• chr9-129868140-C-G
• NM_001110303.4:c.826C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001110303.4(USP20):​c.826C>G​(p.Arg276Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP20 NM_001110303.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP20	NM_001110303.4	c.826C>G	p.Arg276Gly	missense_variant	Exon 11 of 26	ENST00000372429.8	NP_001103773.2
USP20	NM_001008563.5	c.826C>G	p.Arg276Gly	missense_variant	Exon 11 of 26		NP_001008563.2
USP20	NM_006676.8	c.826C>G	p.Arg276Gly	missense_variant	Exon 11 of 25		NP_006667.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP20	ENST00000372429.8	c.826C>G	p.Arg276Gly	missense_variant	Exon 11 of 26	1	NM_001110303.4	ENSP00000361506.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 89 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;T;T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.41	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.80	P;P;P
Vest4		0.64
MutPred		0.48		Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);
MVP		0.43
MPC		0.43
ClinPred		0.78	D
GERP RS		3.3
Varity_R		0.11
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-132630419;