rs534592472
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000310.4(PPT1):c.362+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
PPT1
NM_000310.4 splice_donor_region, intron
NM_000310.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001069
2
Clinical Significance
Conservation
PhyloP100: 1.36
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP6
?
Variant 1-40092041-G-A is Benign according to our data. Variant chr1-40092041-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533953.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.362+4C>T | splice_donor_region_variant, intron_variant | ENST00000642050.2 | |||
PPT1 | NM_001142604.2 | c.125-2529C>T | intron_variant | ||||
PPT1 | NM_001363695.2 | c.362+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.362+4C>T | splice_donor_region_variant, intron_variant | NM_000310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152124Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
2
AN:
152124
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251370Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135856
GnomAD3 exomes
AF:
AC:
12
AN:
251370
Hom.:
AF XY:
AC XY:
6
AN XY:
135856
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461670Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14AN XY: 727150
GnomAD4 exome
AF:
AC:
26
AN:
1461670
Hom.:
Cov.:
33
AF XY:
AC XY:
14
AN XY:
727150
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74436
GnomAD4 genome
?
AF:
AC:
2
AN:
152244
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
74436
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 28, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 31, 2022 | This sequence change falls in intron 3 of the PPT1 gene. It does not directly change the encoded amino acid sequence of the PPT1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs534592472, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533953). 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | PPT1: BP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at