GeneBe

rs4603

Variant names:

Variant summary

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

The NM_002796.3(PSMB4):​c.701T>A​(p.Ile234Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I234T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PSMB4
NM_002796.3 missense

Scores

7
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.82

Publications

51 publications found
Variant links:
Genes affected
PSMB4 (HGNC:9541): (proteasome 20S subunit beta 4) 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. [provided by RefSeq, Jul 2008]
PSMB4 Gene-Disease associations (from GenCC):
  • proteasome-associated autoinflammatory syndrome 3
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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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, 0.877

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002796.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PSMB4
NM_002796.3
MANE Select
c.701T>Ap.Ile234Asn
missense
Exon 6 of 7NP_002787.2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PSMB4
ENST00000290541.7
TSL:1 MANE Select
c.701T>Ap.Ile234Asn
missense
Exon 6 of 7ENSP00000290541.6
PSMB4
ENST00000933662.1
c.584T>Ap.Ile195Asn
missense
Exon 5 of 6ENSP00000603721.1
PSMB4
ENST00000933663.1
c.494T>Ap.Ile165Asn
missense
Exon 5 of 6ENSP00000603722.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Uncertain
0.014
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Benign
-0.74
T
MutationAssessor
Pathogenic
2.9
M
PhyloP100
4.8
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.56
Gain of disorder (P = 0.0465)
MVP
0.68
MPC
1.6
ClinPred
0.99
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.96
gMVP
0.98
Mutation Taster
=45/55
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: rs4603; hg19: chr1-151374025; API