NM_148919.4:c.229G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_148919.4(PSMB8):​c.229G>A​(p.Ala77Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,612,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

PSMB8
NM_148919.4 missense

Scores

8
8
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.10

Publications

1 publications found
Variant links:
Genes affected
PSMB8 (HGNC:9545): (proteasome 20S subunit beta 8) 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 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]
PSMB8 Gene-Disease associations (from GenCC):
  • proteasome-associated autoinflammatory syndrome 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • proteosome-associated autoinflammatory syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSMB8NM_148919.4 linkc.229G>A p.Ala77Thr missense_variant Exon 2 of 6 ENST00000374882.8 NP_683720.2 P28062-1X5CMJ9
PSMB8NM_004159.5 linkc.217G>A p.Ala73Thr missense_variant Exon 2 of 6 NP_004150.1 P28062-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSMB8ENST00000374882.8 linkc.229G>A p.Ala77Thr missense_variant Exon 2 of 6 1 NM_148919.4 ENSP00000364016.4 P28062-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.0000324
AC:
8
AN:
246880
AF XY:
0.0000297
show subpopulations
Gnomad AFR exome
AF:
0.0000658
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000541
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000548
AC:
80
AN:
1460780
Hom.:
0
Cov.:
33
AF XY:
0.0000550
AC XY:
40
AN XY:
726710
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.0000191
AC:
1
AN:
52324
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000665
AC:
74
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000329
AC:
5
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41444
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68022
Other (OTH)
AF:
0.000478
AC:
1
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.535
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000987
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.00000834
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Proteasome-associated autoinflammatory syndrome 1 Uncertain:1
Sep 01, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine with threonine at codon 77 of the PSMB8 protein (p.Ala77Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs774341327, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with PSMB8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autoinflammatory syndrome Uncertain:1
Mar 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
T;T;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Pathogenic
3.9
.;H;.
PhyloP100
7.1
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.2
D;D;D
REVEL
Uncertain
0.49
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.90
MVP
0.87
MPC
1.5
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.81
gMVP
0.90
Mutation Taster
=31/69
disease causing

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

Other links and lift over

dbSNP: rs774341327; hg19: chr6-32810785; API