chr19-38376391-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_002812.5(PSMD8):c.473G>A(p.Arg158His) variant causes a missense change. The variant allele was found at a frequency of 0.000481 in 1,552,496 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00049 ( 1 hom. )
Consequence
PSMD8
NM_002812.5 missense
NM_002812.5 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 5.76
Genes affected
PSMD8 (HGNC:9566): (proteasome 26S subunit, non-ATPase 8) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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 non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040890962).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSMD8 | NM_002812.5 | c.473G>A | p.Arg158His | missense_variant | 3/7 | ENST00000215071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSMD8 | ENST00000215071.9 | c.473G>A | p.Arg158His | missense_variant | 3/7 | 1 | NM_002812.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000514 AC: 83AN: 161564Hom.: 0 AF XY: 0.000602 AC XY: 51AN XY: 84758
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GnomAD4 exome AF: 0.000493 AC: 691AN: 1400322Hom.: 1 Cov.: 34 AF XY: 0.000508 AC XY: 351AN XY: 690756
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GnomAD4 genome AF: 0.000368 AC: 56AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74336
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2021 | The c.473G>A (p.R158H) alteration is located in exon 3 (coding exon 3) of the PSMD8 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the arginine (R) at amino acid position 158 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;.
MutationTaster
Benign
D;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.
Sift4G
Benign
T;T;T;T
Polyphen
B;B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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