rs386833645
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000310.4(PPT1):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000031 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
PPT1
NM_000310.4 start_lost
NM_000310.4 start_lost
Scores
5
4
2
Clinical Significance
Conservation
PhyloP100: 5.74
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000310.4 (PPT1) was described as [Likely_pathogenic] in ClinVar as 206651
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-40097236-C-T is Pathogenic according to our data. Variant chr1-40097236-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40097236-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.3G>A | p.Met1? | start_lost | 1/9 | ENST00000642050.2 | |
PPT1 | NM_001363695.2 | c.3G>A | p.Met1? | start_lost | 1/8 | ||
PPT1 | NM_001142604.2 | c.3G>A | p.Met1? | start_lost | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.3G>A | p.Met1? | start_lost | 1/9 | NM_000310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461536Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727106
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:4
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change affects the initiator methionine of the PPT1 mRNA. The next in-frame methionine is located at codon 41. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 11073228, 11440996). ClinVar contains an entry for this variant (Variation ID: 56193). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects PPT1 function (PMID: 11440996). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 08, 2014 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2021 | The c.3G>A (p.M1?) alteration is located in coding exon 1 of the PPT1 gene and results from a G to A substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This mutation was identified in two individuals with neuronal ceroid lipofuscinosis in conjunction with a second PPT1 variant (Das, 1998). Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2022 | Published functional studies demonstrate a damaging effect suggesting a partial defect in protein expression (Lyly et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10191107, 33561134, 9664077, 17565660, 11440996, 29631617, 11073228) - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2023 | Variant summary: PPT1 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247912 control chromosomes (gnomAD, v2). c.3G>A has been reported in the literature in at least three individuals affected with late-infantile or juvenile-onset Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a greatly reduced protein expression, with a largely preserved specific activity in transfected cells, which was in accordance with the significantly reduced enzyme activity in patient derived cell lines (Das_2001, Lyly_2007, Sima_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
Polyphen
P;.;.;.;.;P;.
Vest4
0.96, 0.96
MutPred
Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);Gain of catalytic residue at M1 (P = 0.0246);
MVP
0.97
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at