rs527236116

chr9-32541967-GTCTC-Gchr9-32541967-GTCTC-GTC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_005802.5(TOPORS):c.2554_2557del(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOPORS NM_005802.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

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: 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: 1 AN: 151894 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461088 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74180

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa Pathogenic:4

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. -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs527236116; hg19: chr9-32541965;