9-37784741-CCCAGTAAACA-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_016042.4(EXOSC3):c.294_303del(p.Val99TrpfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G98G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016042.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOSC3 | NM_016042.4 | c.294_303del | p.Val99TrpfsTer11 | frameshift_variant | 1/4 | ENST00000327304.10 | |
EXOSC3 | NM_001002269.2 | c.294_303del | p.Val99TrpfsTer11 | frameshift_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOSC3 | ENST00000327304.10 | c.294_303del | p.Val99TrpfsTer11 | frameshift_variant | 1/4 | 1 | NM_016042.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1447360Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 719688
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Pontocerebellar hypoplasia type 1B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 29, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | This sequence change creates a premature translational stop signal (p.Val99Trpfs*11) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 22544365). ClinVar contains an entry for this variant (Variation ID: 31690). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at