chr6-32858467-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_002800.5(PSMB9):c.494G>A(p.Gly165Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,612,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PSMB9
NM_002800.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 3.89

Publications

4 publications found

Variant links:

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

PSMB9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 6-32858467-G-A is Pathogenic according to our data. Variant chr6-32858467-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548995.

BP4

Computational evidence support a benign effect (MetaRNN=0.26273108). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002800.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB9	NM_002800.5	MANE Select	c.494G>A	p.Gly165Asp	missense	Exon 5 of 6	NP_002791.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PSMB9	ENST00000374859.3	TSL:1 MANE Select	c.494G>A	p.Gly165Asp	missense	Exon 5 of 6	ENSP00000363993.2
PSMB9	ENST00000395330.6	TSL:3	c.425G>A	p.Gly142Asp	missense	Exon 5 of 6	ENSP00000378739.1
PSMB9	ENST00000464863.1	TSL:2	n.2243G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000406

AC:

AN:

246572

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.000596

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460736

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.0000497

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000700

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000331

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000340

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 3

Pathogenic:2

May 14, 2024

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 27, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 supporting, PM1 moderated, PM2 moderated, PM3 supporting, BP4 supporting

not specified

Uncertain:1

Jun 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PSMB9 c.494G>A (p.Gly165Asp) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 1605926 control chromosomes (i.e. 51 carriers), predominantly at a frequency of 0.00061 within the African or African-American subpopulation in the gnomAD database (v4.1 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in PSMB9 causing Proteasome-Associated Autoinflammatory Syndrome 6, allowing no conclusion about variant significance. The variant, c.494G>A, has been reported in the literature in two siblings affected with Proteasome-Associated Autoinflammatory Syndrome 6 (Brehm_2015), who also carried a frameshift variant in PSMB4 (i.e. another proteosome associated gene); authors proposed an additive effect for the variants, suggesting digenic inheritance. Authors also examined patient derived cells and found normal chymotryptic- and tryptic but somewhat reduced caspase-like activity, which was similar to the findings in healthy fibroblasts when silencing mRNA expression of the respective genes (Brehm_2015). However, these data do not allow clear conclusions about variant significance. The following publication have been ascertained in the context of this evaluation (PMID: 26524591). ClinVar contains an entry for this variant (Variation ID: 548995). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

Eigen

Benign

-0.10

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.82

M_CAP

Benign

0.0062

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.51

PhyloP100

3.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.069

Sift

Benign

0.25

Sift4G

Benign

0.36

Polyphen

0.0040

Vest4

0.69

MVP

0.50

MPC

0.53

ClinPred

0.089

GERP RS

4.8

Varity_R

0.51

gMVP

0.72

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over