rs1184563885

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

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.30
Variant links:
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]

Genome browser will be placed here

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
TPP1NM_000391.4 linkuse as main transcriptc.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
TPP1ENST00000299427.12 linkuse as main transcriptc.1525C>T p.Gln509Ter stop_gained 12/131 NM_000391.4 ENSP00000299427 P1O14773-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251456
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1461878
Hom.:
0
Cov.:
33
AF XY:
0.0000371
AC XY:
27
AN XY:
727242
show subpopulations
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:
0.0000441
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
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
Bravo
AF:
0.0000113

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 submittercurationDepartment Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos UniversityDec 30, 2017- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Oct 14, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCounsylMar 30, 2017- -
Autosomal recessive spinocerebellar ataxia 7 Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJan 25, 2023The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 12, 2021Variant 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
37
DANN
Uncertain
0.99
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
D;D
Vest4
0.81
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1184563885; hg19: chr11-6636123; API