rs137852699

Positions:

chr1-40097210-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000310.4(PPT1):c.29T>A(p.Leu10Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,613,882 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 (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

PPT1
NM_000310.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.35

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]

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-40097210-A-T is Pathogenic according to our data. Variant chr1-40097210-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40097210-A-T is described in Lovd as [Pathogenic]. Variant chr1-40097210-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPT1	NM_000310.4 linkuse as main transcript	c.29T>A	p.Leu10Ter	stop_gained	1/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2 linkuse as main transcript	c.29T>A	p.Leu10Ter	stop_gained	1/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.29T>A	p.Leu10Ter	stop_gained	1/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.29T>A	p.Leu10Ter	stop_gained	1/9		NM_000310.4	ENSP00000493153	P1	P50897-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000798

AC:

AN:

250496

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.000168

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727186

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:

0.000121

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2017	Variant summary: The PPT1 c.29T>A (p.Leu10X) variant results in a premature termination codon, predicted to cause a truncated or absent PPT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study determined less than 10% PPT activity in PBLs in a patient carrying this mutation (Mitchison_1998). One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.451C>T, p.Arg151X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 20/276316 control chromosomes (gnomAD) at a frequency of 0.0000724, which does not exceed the estimated maximal expected allele frequency of a pathogenic PPT1 variant (0.0007331). This variant has been reported in multiple patients with NCL, in both homozygotes and heterozygotes (Das_1998, Mitchison_1998, Stephenson_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	This sequence change creates a premature translational stop signal (p.Leu10*) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs137852699, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with juvenile or infantile neuronal ceroid lipofuscinosis (PMID: 9425237, 9664077, 23539563). ClinVar contains an entry for this variant (Variation ID: 8903). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	Has been reported previously in several families with infantile or juvenile neuronal ceroid lipofuscinosis (NCL) in the compound heterozygous state with a second variant or in the homozygous state (Mitchison et al., 1998; Das et al., 1998; Miller et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate L10X associated with decreased mRNA and enzyme activity levels (Das et al., 2001; Miller et al., 2013).; This variant is associated with the following publications: (PMID: 21990111, 9733046, 11073228, 21704547, 15965709, 9425237, 31741823, 9664077, 23539563, 31440721, 34733232, 11440996) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.29T>A (p.L10*) alteration, located in exon 1 (coding exon 1) of the PPT1 gene, consists of a T to A substitution at nucleotide position 29. This changes the amino acid from a leucine (L) to a stop codon at amino acid position 10. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (21/281870) total alleles studied. The highest observed frequency was 0.02% (20/128290) of European (non-Finnish) alleles. This mutation was reported in the homozygous state in an individual diagnosed with autosomal recessive infantile neuronal ceroid lipofuscinosis (Munroe, 1998). This mutation has also been found in multiple individuals who were compound heterozygotes for p.L10* along with another mutation in PPT1 and diagnosed with juvenile onset neuronal ceroid lipofuscinosis/granular osmiophilic deposits (Mitchison, 1998). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Uncertain

0.46

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

1.0

A;A

Vest4

0.45, 0.40

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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.

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