rs774341327
Variant summary
Our verdict is Uncertain significance. Variant got 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
NM_148919.4 missense
Scores
7
8
2
Clinical Significance
Conservation
PhyloP100: 7.10
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSMB8 | NM_148919.4 | c.229G>A | p.Ala77Thr | missense_variant | 2/6 | ENST00000374882.8 | |
PSMB8 | NM_004159.5 | c.217G>A | p.Ala73Thr | missense_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSMB8 | ENST00000374882.8 | c.229G>A | p.Ala77Thr | missense_variant | 2/6 | 1 | NM_148919.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000324 AC: 8AN: 246880Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134488
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GnomAD4 exome AF: 0.0000548 AC: 80AN: 1460780Hom.: 0 Cov.: 33 AF XY: 0.0000550 AC XY: 40AN XY: 726710
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
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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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
MVP
MPC
1.5
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at