chr6-32858467-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 548995.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null. Variant chr6-32858467-G-A is described in UniProt as null.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB9	NM_002800.5 link	c.494G>A	p.Gly165Asp	missense_variant	Exon 5 of 6	ENST00000374859.3	NP_002791.1	P28065-1A0A1U9X8D7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB9	ENST00000374859.3 link	c.494G>A	p.Gly165Asp	missense_variant	Exon 5 of 6	1	NM_002800.5	ENSP00000363993.2		P28065-1

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

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246572

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134412

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 SAS 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

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000700

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.82

M_CAP

Benign

0.0062

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.51

.;N

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.2

D;D

REVEL

Benign

0.069

Sift

Benign

0.25

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0040

.;B

Vest4

0.69

MVP

0.50

MPC

0.53

ClinPred

0.089

GERP RS

4.8

Varity_R

0.51

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over