rs386833641

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000310.4(PPT1):​c.310A>T​(p.Lys104*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 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 (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPT1
NM_000310.4 stop_gained

Scores

2
1
4

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.996
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 was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-40092097-T-A is Pathogenic according to our data. Variant chr1-40092097-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56189.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40092097-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPT1NM_000310.4 linkc.310A>T p.Lys104* stop_gained Exon 3 of 9 ENST00000642050.2 NP_000301.1 P50897-1
PPT1NM_001363695.2 linkc.310A>T p.Lys104* stop_gained Exon 3 of 8 NP_001350624.1
PPT1NM_001142604.2 linkc.125-2585A>T intron_variant Intron 1 of 5 NP_001136076.1 P50897-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPT1ENST00000642050.2 linkc.310A>T p.Lys104* stop_gained Exon 3 of 9 NM_000310.4 ENSP00000493153.1 P50897-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461816
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33478
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26134
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39696
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53396
Gnomad4 NFE exome
AF:
8.99e-7
AC:
1
AN:
1111972
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60390
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Benign
0.099
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.32
N
GERP RS
1.9
Mutation Taster
=1/199
disease causing (ClinVar)

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: rs386833641; hg19: chr1-40557769; API