rs869312183

Positions:

• chr9-32541986-G-A

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.2539C>T​(p.Arg847Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOPORS NM_005802.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.86

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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-32541986-G-A is Pathogenic according to our data. Variant chr9-32541986-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32541986-G-A is described in Lovd as [Pathogenic]. Variant chr9-32541986-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-32541986-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOPORS	NM_005802.5	c.2539C>T	p.Arg847Ter	stop_gained	3/3	ENST00000360538.7	NP_005793.2
TOPORS	NM_001195622.2	c.2344C>T	p.Arg782Ter	stop_gained	2/2		NP_001182551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOPORS	ENST00000360538.7	c.2539C>T	p.Arg847Ter	stop_gained	3/3	1	NM_005802.5	ENSP00000353735	P3
TOPORS	ENST00000379858.1	c.2344C>T	p.Arg782Ter	stop_gained	2/2	1		ENSP00000369187	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461494 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727028

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 Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2022	ClinVar contains an entry for this variant (Variation ID: 224754). For these reasons, this variant has been classified as Pathogenic. This protein change is located in a region of the TOPORS protein where a significant number of previously reported TOPORS nonsense and frameshift mutations are found (PMID: 18509552, 23950152, 28076437, 17924349). These observations suggest that a previously unreported nonsense or frameshift change within this region may affect protein function, but experiments have not been done to test this possibility. This variant is also known as p.R782X. This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 22581970, 26155838, 28453362). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg847*) in the TOPORS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 199 amino acid(s) of the TOPORS protein. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 199 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33576794, 28453362, 26155838, 22581970, 26872967) -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Jan 30, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
Vest4		0.76
GERP RS		3.6

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: rs869312183; hg19: chr9-32541984;