rs750533343

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000310.4(PPT1):c.175G>A(p.Glu59Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E59E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

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]

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain Palmitoyl-protein thioesterase 1 (size 278) in uniprot entity PPT1_HUMAN there are 91 pathogenic changes around while only 6 benign (94%) in NM_000310.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4 link	c.175G>A	p.Glu59Lys	missense_variant	Exon 2 of 9	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 link	c.175G>A	p.Glu59Lys	missense_variant	Exon 2 of 8		NP_001350624.1
PPT1	NM_001142604.2 link	c.125-2945G>A		intron_variant	Intron 1 of 5		NP_001136076.1	P50897-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 link	c.175G>A	p.Glu59Lys	missense_variant	Exon 2 of 9		NM_000310.4	ENSP00000493153.1		P50897-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251442

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000376

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 59 of the PPT1 protein (p.Glu59Lys). This variant is present in population databases (rs750533343, gnomAD 0.04%). 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: 206640). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PPT1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

.;D;D;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.71

D;D;D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.8

M;.;.;.;.;.

PrimateAI

Uncertain

0.61

REVEL

Pathogenic

0.66

Polyphen

0.041

B;.;.;.;.;.

MutPred

0.64

Gain of MoRF binding (P = 0.0021);.;.;Gain of MoRF binding (P = 0.0021);Gain of MoRF binding (P = 0.0021);Gain of MoRF binding (P = 0.0021);

MVP

0.98

MPC

0.43

ClinPred

0.56

GERP RS

5.4

Varity_R

0.67

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over