rs1184563885
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000299427.12(TPP1):c.1525C>T(p.Gln509Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
TPP1
ENST00000299427.12 stop_gained
ENST00000299427.12 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.30
Genes affected
TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]
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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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-6614892-G-A is Pathogenic according to our data. Variant chr11-6614892-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6614892-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.1525C>T | p.Gln509Ter | stop_gained | 12/13 | ENST00000299427.12 | NP_000382.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1525C>T | p.Gln509Ter | stop_gained | 12/13 | 1 | NM_000391.4 | ENSP00000299427 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27AN XY: 727242
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 30, 2017 | - - |
Autosomal recessive spinocerebellar ataxia 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The homozygous p.Gln509Ter variant in TPP1 was identified by our study in one individual with neurodegenerative disease with cerebellar atrophy. The p.Gln509Ter variant in TPP1 has been previously reported in 5 unrelated individuals with TPP1-related neurologic disease (PMID: 17690061, PMID: 10862088, PMID: 27217339) and segregated with disease in 7 affected relatives from three families (PMID: 17690061, PMID: 10862088), but has been identified in 0.003% (3/113742) of European (non-Finnish) chromosomes by Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1184563885). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 previously reported affected individuals (PMID: 17690061, PMID: 10862088, PMID: 27217339), 3 were homozygotes (PMID: 17690061, PMID: 10862088) and 2 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 10862088, ClinVar Variation ID: 2643; PMID: 27217339, ClinVar Variation ID: 2645), which increases the likelihood that the p.Gln509Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 551316) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 509. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TPP1 gene is an established disease mechanism of autosomal recessive TPP1-related neurologic disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive TPP1-related neurologic disease. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change creates a premature translational stop signal (p.Gln509*) in the TPP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the TPP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (PMID: 10862088). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551316). For these reasons, this variant has been classified as Pathogenic. - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 12, 2021 | Variant summary: TPP1 c.1525C>T (p.Gln509X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One study reports that this results in a mutant allele that is translated into a shorter peptide, lacking the last 54 amino acids of the encoded protein (Tessa_2000). The variant allele was found at a frequency of 1.2e-05 in 251456 control chromosomes. c.1525C>T has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Tessa_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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