NM_017414.4:c.652C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017414.4(USP18):c.652C>T(p.Gln218*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017414.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USP18 | ENST00000215794.8 | c.652C>T | p.Gln218* | stop_gained | Exon 7 of 11 | 1 | NM_017414.4 | ENSP00000215794.7 | ||
USP18 | ENST00000699060.1 | c.652C>T | p.Gln218* | stop_gained | Exon 7 of 10 | ENSP00000514107.1 | ||||
USP18 | ENST00000699061.1 | n.398C>T | non_coding_transcript_exon_variant | Exon 4 of 6 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1452348Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 721344
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Pseudo-TORCH syndrome 2 Pathogenic:2
The heterozygous p.Gln218Ter variant in USP18 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 417775), in two siblings with pseudo-TORCH syndrome 2 (PMID: 27325888). Familial exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 417775). These individuals along with 3 homozygous affected siblings from another family, were reported in the literature (PMID: 27325888). Of these 5 affected individuals (PMID: 27325888), 3 were homozygotes and 2 were compound heterozygotes who carried a likely pathogenic variant (ClinVar Variation ID: 417775) in trans, which increases the likelihood that the p.Gln218Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 417774) and has been interpreted as pathogenic by OMIM. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 218, which is predicted to lead to a truncated or absent protein. Loss of function of the USP18 gene is strongly associated to autosomal recessive pseudo-TORCH syndrome 2 (PMID: 27325888). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive pseudo-TORCH syndrome 2. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3, PP1 (Richards 2015). -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at