rs386833665

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000310.4(PPT1):ā€‹c.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

Scores

13
5
1

Clinical Significance

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

Conservation

PhyloP100: 7.35
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 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
PPT1NM_000310.4 linkuse as main transcriptc.739T>C p.Tyr247His missense_variant 8/9 ENST00000642050.2 NP_000301.1
PPT1NM_001142604.2 linkuse as main transcriptc.430T>C p.Tyr144His missense_variant 5/6 NP_001136076.1
PPT1NM_001363695.2 linkuse as main transcriptc.726+1659T>C intron_variant NP_001350624.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPT1ENST00000642050.2 linkuse as main transcriptc.739T>C p.Tyr247His missense_variant 8/9 NM_000310.4 ENSP00000493153 P1P50897-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251396
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135872
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461820
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727212
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:
0.00000899
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingBaylor GeneticsMar 12, 2024- -
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 08, 2023For 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 submitterclinical testingEurofins Ntd Llc (ga)Dec 22, 2016- -
Neuronal ceroid lipofuscinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 06, 2023Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.;.;.;.;.;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
H;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-4.8
.;.;D;.;.;D;.
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
.;.;D;.;.;D;.
Sift4G
Pathogenic
0.0
.;.;D;.;.;D;.
Polyphen
1.0
D;.;.;.;.;D;.
Vest4
0.82, 0.74
MutPred
0.91
Gain of disorder (P = 0.0296);.;.;.;Gain of disorder (P = 0.0296);.;.;
MVP
1.0
MPC
0.66
ClinPred
0.99
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.95
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs386833665; hg19: chr1-40542573; API