9-129858488-G-C

Variant names:

• chr9-129858488-G-C
• rs191133247
• NM_001110303.4:c.220G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001110303.4(USP20):​c.220G>C​(p.Val74Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V74M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: USP20 NM_001110303.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.93
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110303.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP20	NM_001110303.4	MANE Select	c.220G>C	p.Val74Leu	missense	Exon 6 of 26	NP_001103773.2	Q9Y2K6
	USP20	NM_001008563.5		c.220G>C	p.Val74Leu	missense	Exon 6 of 26	NP_001008563.2	Q9Y2K6
	USP20	NM_006676.8		c.220G>C	p.Val74Leu	missense	Exon 6 of 25	NP_006667.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP20	ENST00000372429.8	TSL:1 MANE Select	c.220G>C	p.Val74Leu	missense	Exon 6 of 26	ENSP00000361506.3	Q9Y2K6
	USP20	ENST00000315480.9	TSL:1	c.220G>C	p.Val74Leu	missense	Exon 6 of 25	ENSP00000313811.4	Q9Y2K6
	USP20	ENST00000358355.5	TSL:1	c.220G>C	p.Val74Leu	missense	Exon 6 of 26	ENSP00000351122.1	Q9Y2K6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249536 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461844 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.10	N
PhyloP100		9.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.30
Sift	Benign	0.16	T
Sift4G	Benign	0.53	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.70		Loss of methylation at K69 (P = 0.0814)
MVP		0.66
MPC		0.47
ClinPred		0.82	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.65
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs191133247; hg19: chr9-132620767;