rs137852698
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000310.4(PPT1):c.656T>A(p.Leu219Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L219L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
PPT1
NM_000310.4 missense
NM_000310.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 8.98
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000310.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 1-40078630-A-T is Pathogenic according to our data. Variant chr1-40078630-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 8902.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40078630-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.656T>A | p.Leu219Gln | missense_variant | 7/9 | ENST00000642050.2 | NP_000301.1 | |
PPT1 | NM_001363695.2 | c.656T>A | p.Leu219Gln | missense_variant | 7/8 | NP_001350624.1 | ||
PPT1 | NM_001142604.2 | c.347T>A | p.Leu116Gln | missense_variant | 4/6 | NP_001136076.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.656T>A | p.Leu219Gln | missense_variant | 7/9 | NM_000310.4 | ENSP00000493153.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1998 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
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
Pathogenic
.;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;.;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;.;.;D;.
Sift4G
Pathogenic
.;.;.;.;.;D;.
Polyphen
D;.;.;.;.;D;.
Vest4
0.93
MutPred
Gain of disorder (P = 0.0211);.;.;Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);.;.;
MVP
1.0
MPC
0.59
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at