rs527236116
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_005802.5(TOPORS):βc.2554_2557delβ(p.Glu852GlnfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
TOPORS
NM_005802.5 frameshift
NM_005802.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.81
Genes affected
TOPORS (HGNC:21653): (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) This gene encodes a nuclear protein which is serine and arginine rich, and contains a RING-type zinc finger domain. It is highly expressed in the testis, and functions as an ubiquitin-protein E3 ligase. Mutations in this gene are associated with retinitis pigmentosa type 31. Alternatively spliced transcript variants, encoding different isoforms, have been observed for this locus. [provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 9-32541967-GTCTC-G is Pathogenic according to our data. Variant chr9-32541967-GTCTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32541967-GTCTC-G is described in Lovd as [Pathogenic]. Variant chr9-32541967-GTCTC-G is described in Lovd as [Pathogenic]. Variant chr9-32541967-GTCTC-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOPORS | NM_005802.5 | c.2554_2557del | p.Glu852GlnfsTer13 | frameshift_variant | 3/3 | ENST00000360538.7 | |
TOPORS | NM_001195622.2 | c.2359_2362del | p.Glu787GlnfsTer13 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOPORS | ENST00000360538.7 | c.2554_2557del | p.Glu852GlnfsTer13 | frameshift_variant | 3/3 | 1 | NM_005802.5 | P3 | |
TOPORS | ENST00000379858.1 | c.2359_2362del | p.Glu787GlnfsTer13 | frameshift_variant | 2/2 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151894Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461088Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726840
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa Pathogenic:4
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Glu852GlnfsTer13 variant in TOPORS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Retinitis pigmentosa 31 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The TOPORS c.2554_2557del variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 15, 2018 | The c.2554_2557delGAGA variant in the TOPORS gene has been reported previously in an individual with retinitis pigmentosa (Sullivan et al., 2013). The c.2554_2557delGAGA variant causes a frameshift starting with codon Glutamic Acid 852, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Glu852GlnfsX13. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 194 amino acids are lost and replaced with 12 incorrect amino acids. The c.2554_2557delGAGA variant is observed in 1/14,976 alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.2554_2557delGAGA as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change creates a premature translational stop signal (p.Glu852Glnfs*13) in the TOPORS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the TOPORS protein. This variant is present in population databases (rs527236116, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 23950152; Invitae). ClinVar contains an entry for this variant (Variation ID: 143130). This variant is located in a region of the TOPORS protein where a significant number of TOPORS nonsense and frameshift mutations have been reported in association with autosomal dominant retinitis pigmentosa (PMID: 35579903, 17924349, 32531858). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 08, 2019 | - - |
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