rs1114167444
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5
The NM_002816.5(PSMD12):c.909-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PSMD12
NM_002816.5 splice_acceptor
NM_002816.5 splice_acceptor
Scores
5
1
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 7.59
Genes affected
PSMD12 (HGNC:9557): (proteasome 26S subunit, non-ATPase 12) 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 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.4, offset of 13, new splice context is: ttttcggggatcttttaaAGctt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 17-67344782-T-C is Pathogenic according to our data. Variant chr17-67344782-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 427782.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-67344782-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSMD12 | NM_002816.5 | c.909-2A>G | splice_acceptor_variant | ENST00000356126.8 | |||
PSMD12 | NM_001316341.2 | c.732-2A>G | splice_acceptor_variant | ||||
PSMD12 | NM_174871.4 | c.849-2A>G | splice_acceptor_variant | ||||
PSMD12 | XM_047436440.1 | c.939A>G | p.Ser313= | synonymous_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSMD12 | ENST00000356126.8 | c.909-2A>G | splice_acceptor_variant | 1 | NM_002816.5 | P1 | |||
PSMD12 | ENST00000584008.5 | c.*1064-2A>G | splice_acceptor_variant, NMD_transcript_variant | 1 | |||||
PSMD12 | ENST00000357146.4 | c.849-2A>G | splice_acceptor_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1420938Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 704866
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1420938
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
704866
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Stankiewicz-Isidor syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -15
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at