rs797045567
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_016042.4(EXOSC3):c.572G>A(p.Gly191Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G191C) has been classified as Pathogenic.
Frequency
Consequence
NM_016042.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOSC3 | NM_016042.4 | c.572G>A | p.Gly191Asp | missense_variant | 3/4 | ENST00000327304.10 | |
EXOSC3 | NM_001002269.2 | c.475-1160G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOSC3 | ENST00000327304.10 | c.572G>A | p.Gly191Asp | missense_variant | 3/4 | 1 | NM_016042.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251422Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461666Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727138
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 1B Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics, University of Leipzig | Mar 07, 2019 | The variant was detected in compound heterozygous state in two siblings with pontocerebellar hypoplasia. Another missense variant c.571G>T, that leads to the same amino acid change p.(Gly191Asp) has already been described as pathogenic Halevy (2014) J Neurol 261: 2165 PubMed: 25149867 and has been functionally characterized Gillespie (2017) RNA 23: 466 PubMed: 28053271. The allele frequency of the variant c.572G>A in gnomAD is 0.008%. In summary we evaluate the variant NM_016042.3:c.572G>A, p.(Gly191Asp) as likely pathogenic based on the ACMG criteria. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 191 of the EXOSC3 protein (p.Gly191Asp). This variant is present in population databases (rs797045567, gnomAD 0.002%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 30986545, 31692161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 210965). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXOSC3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | EXOSC3: PM3:Strong, PM2, PM5, PP1 - |
not specified Uncertain:1
Uncertain significance, flagged submission | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 16, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at