11-6617437-C-CA
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_000391.4(TPP1):c.381-10_381-9insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,016 control chromosomes in the GnomAD database, including 325 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..
Frequency
Genomes: 𝑓 0.025 ( 159 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 166 hom. )
Consequence
TPP1
NM_000391.4 splice_polypyrimidine_tract, intron
NM_000391.4 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.55
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 Benign. Variant got -16 ACMG points.
BP6
Variant 11-6617437-C-CA is Benign according to our data. Variant chr11-6617437-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 197664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.381-10_381-9insT | splice_polypyrimidine_tract_variant, intron_variant | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.381-10_381-9insT | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0253 AC: 3854AN: 152042Hom.: 159 Cov.: 32
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GnomAD3 exomes AF: 0.00689 AC: 1731AN: 251316Hom.: 63 AF XY: 0.00519 AC XY: 705AN XY: 135852
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GnomAD4 exome AF: 0.00274 AC: 4011AN: 1461856Hom.: 166 Cov.: 34 AF XY: 0.00239 AC XY: 1741AN XY: 727226
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GnomAD4 genome AF: 0.0254 AC: 3869AN: 152160Hom.: 159 Cov.: 32 AF XY: 0.0244 AC XY: 1818AN XY: 74394
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 30, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 28, 2018 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 03, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2022 | Variant summary: TPP1 c.381-10dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 282666 control chromosomes, predominantly at a frequency of 0.089 within the African or African-American subpopulation in the gnomAD database, including 102 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 45 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.381-10dupT in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=5), likely benign (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Neuronal ceroid lipofuscinosis 2 Pathogenic:1Benign:1
Likely pathogenic, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Feb 05, 2018 | The observed variant g.7024dupT was neither found in 1000 Genomes nor in ExAC databases. The in-silico prediction of the given variant is disease causing by MutationTaster2. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Neuronal Ceroid-Lipofuscinosis, Recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at