rs386833664
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000310.4(PPT1):c.727-2A>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,784 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_000310.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.727-2A>T | splice_acceptor_variant, intron_variant | ENST00000642050.2 | NP_000301.1 | |||
PPT1 | NM_001363695.2 | c.726+1645A>T | intron_variant | NP_001350624.1 | ||||
PPT1 | NM_001142604.2 | c.418-2A>T | splice_acceptor_variant, intron_variant | NP_001136076.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.727-2A>T | splice_acceptor_variant, intron_variant | NM_000310.4 | ENSP00000493153.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251382Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461784Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727208
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:3
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2023 | This sequence change affects an acceptor splice site in intron 7 of the PPT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833664, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). This variant is also known as T (IVS7, -2). ClinVar contains an entry for this variant (Variation ID: 56213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2017 | A c.727-2 A>T variant that is likely pathogenic has been identified in the PPT1 gene. The c.727-2 A>T variant was previously reported in one patient with infantile neuronal ceroid lipofuscinoses, with known palmitoyl-protein thioesterase deficiency, who also harbored a second PPT1 pathogenic variant, however phase was not reported (Das et al., 1998). The c.727-2 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.727-2 A>T splice site variant gene destroys the canonical splice acceptor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 28, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at