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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PPT1
NM_000310.4 splice_acceptor, intron

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.97
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07709012 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 17, new splice context is: ctgtggtttggattttacAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-40076915-T-A is Pathogenic according to our data. Variant chr1-40076915-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40076915-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PPT1NM_000310.4 linkuse as main transcriptc.727-2A>T splice_acceptor_variant, intron_variant ENST00000642050.2 NP_000301.1 P50897-1
PPT1NM_001363695.2 linkuse as main transcriptc.726+1645A>T intron_variant NP_001350624.1
PPT1NM_001142604.2 linkuse as main transcriptc.418-2A>T splice_acceptor_variant, intron_variant NP_001136076.1 P50897-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPT1ENST00000642050.2 linkuse as main transcriptc.727-2A>T splice_acceptor_variant, intron_variant NM_000310.4 ENSP00000493153.1 P50897-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251382
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461784
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 04, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2023This 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 submitterclinical testingGeneDxJan 31, 2017A 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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMar 28, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.73
Position offset: -19
DS_AL_spliceai
1.0
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833664; hg19: chr1-40542587; API