6-32840975-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_148919.4(PSMB8):c.815G>A(p.Arg272Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272W) has been classified as Uncertain significance.
Frequency
Consequence
NM_148919.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSMB8 | NM_148919.4 | c.815G>A | p.Arg272Gln | missense_variant | 6/6 | ENST00000374882.8 | |
PSMB8 | NM_004159.5 | c.803G>A | p.Arg268Gln | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSMB8 | ENST00000374882.8 | c.815G>A | p.Arg272Gln | missense_variant | 6/6 | 1 | NM_148919.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251480Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135916
GnomAD4 exome AF: 0.0000370 AC: 54AN: 1461086Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21AN XY: 726868
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74426
ClinVar
Submissions by phenotype
Proteasome-associated autoinflammatory syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jul 12, 2022 | This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.04% (18/41414) (https://gnomad.broadinstitute.org/variant/6-32840975-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:465423). This variant amino acid Glutamine (Gln) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 272 of the PSMB8 protein (p.Arg272Gln). This variant is present in population databases (rs368551668, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PSMB8-related conditions. ClinVar contains an entry for this variant (Variation ID: 465423). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at