rs587780333
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016042.4(EXOSC3):c.112del(p.Glu38AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
EXOSC3
NM_016042.4 frameshift
NM_016042.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.63
Genes affected
EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 9-37784932-TC-T is Pathogenic according to our data. Variant chr9-37784932-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 129023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOSC3 | NM_016042.4 | c.112del | p.Glu38AsnfsTer16 | frameshift_variant | 1/4 | ENST00000327304.10 | |
EXOSC3 | NM_001002269.2 | c.112del | p.Glu38AsnfsTer16 | frameshift_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOSC3 | ENST00000327304.10 | c.112del | p.Glu38AsnfsTer16 | frameshift_variant | 1/4 | 1 | NM_016042.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000415 AC: 1AN: 241002Hom.: 0 AF XY: 0.00000763 AC XY: 1AN XY: 131042
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GnomAD4 exome AF: 0.00000823 AC: 12AN: 1458900Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 725558
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pontocerebellar hypoplasia type 1B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 23, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change creates a premature translational stop signal (p.Glu38Asnfs*16) in the EXOSC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXOSC3 are known to be pathogenic (PMID: 22544365, 23284067, 24524299). This variant is present in population databases (rs587780333, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with EXOSC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 129023). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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