rs1349528345
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000310.4(PPT1):c.776_777insA(p.Glu260GlyfsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
PPT1
NM_000310.4 frameshift
NM_000310.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.28
Genes affected
PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]
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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 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-40076863-C-CT is Pathogenic according to our data. Variant chr1-40076863-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.776_777insA | p.Glu260GlyfsTer35 | frameshift_variant | 8/9 | ENST00000642050.2 | |
PPT1 | NM_001142604.2 | c.467_468insA | p.Glu157GlyfsTer35 | frameshift_variant | 5/6 | ||
PPT1 | NM_001363695.2 | c.726+1696_726+1697insA | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.776_777insA | p.Glu260GlyfsTer35 | frameshift_variant | 8/9 | NM_000310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 30
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PPT1 protein in which other variant(s) (p.Leu271*) have been determined to be pathogenic (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. ClinVar contains an entry for this variant (Variation ID: 557103). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 23857568). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu260Glyfs*35) in the PPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the PPT1 protein. - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 30, 2020 | ACMG codes:PVS1, PM2, PM3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2018 | - - |
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