11-6614865-C-T
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>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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>A | splice_donor_variant | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1551+1G>A | splice_donor_variant | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251440Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | 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. This variant is present in population databases (rs786204553, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 20820830, 26032578). ClinVar contains an entry for this variant (Variation ID: 188909). 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. This variant disrupts a region of the TPP1 protein in which other variant(s) (p.Gly535Arg) have been determined to be pathogenic (PMID: 23266810). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 05, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2015 | The c.1551+1 G>A splice site variant in the TPP1 gene has been previously reported in an individual with cLINCL who had a second TPP1 variant on the other allele (Wang et al., 2011). This pathogenic variant destroys the canonical splice donor site in intron 12, and is expected to cause abnormal gene splicing. Additionally, different variants at the same position (c.1551+1 G>T, c.1551+1 G>C) have been reported previously in association with cLINCL (Stenson et al., 2014). Therefore, c.1551+1 G>A is considered to be a pathogenic variant. - |
Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 31, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at