rs386833665
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000310.4(PPT1):āc.739T>Cā(p.Tyr247His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,820 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 (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
PPT1
NM_000310.4 missense
NM_000310.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.35
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 16 ACMG points.
PM1
In a chain Palmitoyl-protein thioesterase 1 (size 278) in uniprot entity PPT1_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000310.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 1-40076901-A-G is Pathogenic according to our data. Variant chr1-40076901-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40076901-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.739T>C | p.Tyr247His | missense_variant | 8/9 | ENST00000642050.2 | NP_000301.1 | |
PPT1 | NM_001142604.2 | c.430T>C | p.Tyr144His | missense_variant | 5/6 | NP_001136076.1 | ||
PPT1 | NM_001363695.2 | c.726+1659T>C | intron_variant | NP_001350624.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.739T>C | p.Tyr247His | missense_variant | 8/9 | NM_000310.4 | ENSP00000493153 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251396Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461820Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727212
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr247 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996, 29631617). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 56214). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077, 23857568). This variant is present in population databases (rs386833665, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 247 of the PPT1 protein (p.Tyr247His). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 22, 2016 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 06, 2023 | Variant summary: PPT1 c.739T>C (p.Tyr247His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251396 control chromosomes (gnomAD). c.739T>C has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (examples: Das_1998 and Miller_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Das_2001). A different variant affecting the same residue c.740A>G (p.Tyr247Cys) is classified likely pathogenic in ClinVar (ID 379909), suggesting this residue may be critical for the normal protein function. The following publications have been ascertained in the context of this evaluation (PMID: 11440996, 9664077, 23857568, 29631617, 11073228). Two 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 likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;D;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;.;.;D;.
Sift4G
Pathogenic
.;.;D;.;.;D;.
Polyphen
D;.;.;.;.;D;.
Vest4
0.82, 0.74
MutPred
Gain of disorder (P = 0.0296);.;.;.;Gain of disorder (P = 0.0296);.;.;
MVP
1.0
MPC
0.66
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