chr9-32541397-TCA-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_ModeratePP5BS1_SupportingBS2
The NM_005802.5(TOPORS):c.3126_3127delTG(p.Cys1042fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005802.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TOPORS | ENST00000360538.7 | c.3126_3127delTG | p.Cys1042fs | frameshift_variant | Exon 3 of 3 | 1 | NM_005802.5 | ENSP00000353735.2 | ||
TOPORS | ENST00000379858.1 | c.2931_2932delTG | p.Cys977fs | frameshift_variant | Exon 2 of 2 | 1 | ENSP00000369187.1 | |||
ENSG00000288684 | ENST00000681750.1 | c.-45+9375_-45+9376delTG | intron_variant | Intron 3 of 19 | ENSP00000506413.1 | |||||
ENSG00000288684 | ENST00000680198.1 | c.198+9375_198+9376delTG | intron_variant | Intron 2 of 18 | ENSP00000505143.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251336Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135824
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461832Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727206
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Cys1042*) in the TOPORS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the TOPORS protein. This variant is present in population databases (rs776001696, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of retinitis pigmentosa (Invitae). ClinVar contains an entry for this variant (Variation ID: 940703). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Retinitis pigmentosa 31 Uncertain:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at