rs17587

Variant names:

• chr6-32857313-G-A
• rs17587
• NM_002800.5:c.179G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32857313-G-A
• chr6-32857313-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002800.5(PSMB9):​c.179G>A​(p.Arg60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,611,312 control chromosomes in the GnomAD database, including 57,743 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4697 hom., cov: 31)
  • Exomes 𝑓: 0.27 (53046 hom.)
• Consequence: PSMB9 NM_002800.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.107
• Publications: 101 publications found

Genes affected

PSMB9 (HGNC:9546): (proteasome 20S subunit beta 9) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. [provided by RefSeq, Mar 2010]

PSMB9 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 3

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026171207).
• BP6: Variant 6-32857313-G-A is Benign according to our data. Variant chr6-32857313-G-A is described in ClinVar as Benign. ClinVar VariationId is 1327454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB9	NM_002800.5	c.179G>A	p.Arg60His	missense_variant	Exon 3 of 6	ENST00000374859.3	NP_002791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB9	ENST00000374859.3	c.179G>A	p.Arg60His	missense_variant	Exon 3 of 6	1	NM_002800.5	ENSP00000363993.2

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37402 AN: 151680 Hom.: 4703 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.243 AC: 59817 AN: 245712 AF XY: 0.244

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.267 AC: 389043 AN: 1459520 Hom.: 53046 Cov.: 40 AF XY: 0.265 AC XY: 192647 AN XY: 726088

African (AFR) AF: 0.223 AC: 7446 AN: 33428

American (AMR) AF: 0.229 AC: 10224 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6819 AN: 26110

East Asian (EAS) AF: 0.216 AC: 8560 AN: 39624

South Asian (SAS) AF: 0.197 AC: 16937 AN: 86142

European-Finnish (FIN) AF: 0.216 AC: 11252 AN: 52120

Middle Eastern (MID) AF: 0.348 AC: 1997 AN: 5744

European-Non Finnish (NFE) AF: 0.278 AC: 309346 AN: 1111350

Other (OTH) AF: 0.273 AC: 16462 AN: 60340

GnomAD4 genome AF: 0.246 AC: 37389 AN: 151792 Hom.: 4697 Cov.: 31 AF XY: 0.241 AC XY: 17885 AN XY: 74180

African (AFR) AF: 0.220 AC: 9100 AN: 41376

American (AMR) AF: 0.243 AC: 3704 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 854 AN: 3468

East Asian (EAS) AF: 0.196 AC: 1012 AN: 5164

South Asian (SAS) AF: 0.189 AC: 912 AN: 4814

European-Finnish (FIN) AF: 0.217 AC: 2278 AN: 10482

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18624 AN: 67924

Other (OTH) AF: 0.272 AC: 572 AN: 2104

Alfa AF: 0.267 Hom.: 24897

Bravo AF: 0.247

TwinsUK AF: 0.287 AC: 1063

ALSPAC AF: 0.292 AC: 1126

ESP6500AA AF: 0.215 AC: 649

ESP6500EA AF: 0.267 AC: 1444

ExAC AF: 0.244 AC: 28687

Asia WGS AF: 0.209 AC: 729 AN: 3478

EpiCase AF: 0.290

EpiControl AF: 0.289

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 14, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied by a panel of primary immunodeficiencies. Number of patients: 42. Only high quality variants are reported. -

PSMB9-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Proteasome-associated autoinflammatory syndrome 3 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.047	N
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;.;L
PhyloP100		0.11
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.084
MPC		0.51
ClinPred		0.0010	T
GERP RS		-3.8
Varity_R		0.15
gMVP		0.61
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17587; hg19: chr6-32825090; COSMIC: COSV62754598; COSMIC: COSV62754598;