11-6614865-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000391.4(TPP1):c.1551+1G>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000391.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.1551+1G>C | splice_donor_variant | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1551+1G>C | splice_donor_variant | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251440Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | Disruption of this splice site has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 20820830, 23374165, 26032578). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 12 of the TPP1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 370214). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TPP1 protein in which other variant(s) (p.Trp542*) have been determined to be pathogenic (PMID: 31283065; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | Observed in a patient with neuronal ceroid lipofuscinosis; however, no further clinical information was provided (Santorelli et al., 2013); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23374165) - |
Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at