9-129858510-T-G

Variant names:

• chr9-129858510-T-G
• rs2033339954
• NM_001110303.4:c.242T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001110303.4(USP20):​c.242T>G​(p.Leu81Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USP20 NM_001110303.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP20	NM_001110303.4	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 26	ENST00000372429.8	NP_001103773.2
USP20	NM_001008563.5	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 26		NP_001008563.2
USP20	NM_006676.8	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 25		NP_006667.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP20	ENST00000372429.8	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 26	1	NM_001110303.4	ENSP00000361506.3
USP20	ENST00000315480.9	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 25	1		ENSP00000313811.4
USP20	ENST00000358355.5	c.242T>G	p.Leu81Arg	missense_variant	Exon 6 of 26	1		ENSP00000351122.1
USP20	ENST00000494971.2	n.466T>G		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242T>G (p.L81R) alteration is located in exon 6 (coding exon 4) of the USP20 gene. This alteration results from a T to G substitution at nucleotide position 242, causing the leucine (L) at amino acid position 81 to be replaced by an arginine (R). 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;.;T
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.082	B;B;B
Vest4		0.64
MutPred		0.78		Gain of catalytic residue at L81 (P = 0.0071);Gain of catalytic residue at L81 (P = 0.0071);Gain of catalytic residue at L81 (P = 0.0071);
MVP		0.59
MPC		0.53
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.89

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: rs2033339954; hg19: chr9-132620789;