9-129863223-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001110303.4(USP20):c.535C>T(p.Leu179=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000982 in 1,548,252 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (11 hom.)
• Consequence: USP20 NM_001110303.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.14

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 9-129863223-C-T is Benign according to our data. Variant chr9-129863223-C-T is described in ClinVar as [Benign]. Clinvar id is 713867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00498 (758/152294) while in subpopulation AFR AF= 0.0176 (731/41562). AF 95% confidence interval is 0.0165. There are 4 homozygotes in gnomad4. There are 374 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP20	NM_001110303.4	c.535C>T	p.Leu179=	synonymous_variant	9/26	ENST00000372429.8
USP20	NM_001008563.5	c.535C>T	p.Leu179=	synonymous_variant	9/26
USP20	NM_006676.8	c.535C>T	p.Leu179=	synonymous_variant	9/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP20	ENST00000372429.8	c.535C>T	p.Leu179=	synonymous_variant	9/26	1	NM_001110303.4	P1
USP20	ENST00000315480.9	c.535C>T	p.Leu179=	synonymous_variant	9/25	1		P1
USP20	ENST00000358355.5	c.535C>T	p.Leu179=	synonymous_variant	9/26	1		P1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152176 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00104 AC: 163 AN: 156788 Hom.: 0 AF XY: 0.000770 AC XY: 64 AN XY: 83154

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000874

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000680

GnomAD4 exome AF: 0.000546 AC: 762 AN: 1395958 Hom.: 11 Cov.: 31 AF XY: 0.000442 AC XY: 304 AN XY: 688410

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.000751

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000558

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00502 AC XY: 374 AN XY: 74460

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00281 Hom.: 2

Bravo AF: 0.00567

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Aug 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	11
Dann	Benign	0.93

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: rs182928178; hg19: chr9-132625502;