rs374550999
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 13P and 5B. PM1PM5PP3PP5_Very_StrongBP4BS2
The NM_016042.4(EXOSC3):c.238G>T(p.Val80Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,608,334 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign 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. V80L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_016042.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOSC3 | NM_016042.4 | c.238G>T | p.Val80Phe | missense_variant | 1/4 | ENST00000327304.10 | |
EXOSC3 | NM_001002269.2 | c.238G>T | p.Val80Phe | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOSC3 | ENST00000327304.10 | c.238G>T | p.Val80Phe | missense_variant | 1/4 | 1 | NM_016042.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000900 AC: 137AN: 152252Hom.: 6 Cov.: 32
GnomAD3 exomes AF: 0.000153 AC: 36AN: 234882Hom.: 0 AF XY: 0.000132 AC XY: 17AN XY: 128502
GnomAD4 exome AF: 0.0000831 AC: 121AN: 1455964Hom.: 1 Cov.: 30 AF XY: 0.0000773 AC XY: 56AN XY: 724310
GnomAD4 genome ? AF: 0.000899 AC: 137AN: 152370Hom.: 6 Cov.: 32 AF XY: 0.000953 AC XY: 71AN XY: 74506
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 1B Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 80 of the EXOSC3 protein (p.Val80Phe). This variant is present in population databases (rs374550999, gnomAD 0.04%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 23975261, 25809939). 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: 129024). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 21, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2021 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 23975261, 24524299, 25809939, 29656927, 29093021, 27219052, 34532947, 34426522) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Pontoneocerebellar hypoplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 10, 2016 | The p.Val80Phe variant in EXOSC3 has been reported in 2 families with pontocereb ellar hypoplasia in the compound heterozygous state (Zanni 2013; Li 2013) and in one of the families the variant segregated in the 2 affected siblings (Zanni 20 13). This variant has been described in 0.05% (7/14042) of South Asian chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs 374550999). Although this variant has been seen in the general population, its f requency is low enough to be consistent with a recessive carrier frequency. Com putational prediction tools and conservation analysis suggest the variant may im pact the protein function, though this information is not predictive enough to d etermine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val80Phe variant is likely path ogenic for pontocerebellar hypoplasia in an autosomal recessive manner based upo n allelic observations in affected individuals. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at