NM_000310.4:c.125-15T>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_000310.4(PPT1):c.125-15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PPT1
NM_000310.4 intron

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.967

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Myriad Women’s Health

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-40092522-A-C is Pathogenic according to our data. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40092522-A-C is described in CliVar as Likely_pathogenic. Clinvar id is 56177.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4 link	c.125-15T>G	intron_variant	Intron 1 of 8	ENST00000642050.2	NP_000301.1	P50897-1
PPT1	NM_001363695.2 link	c.125-15T>G	intron_variant	Intron 1 of 7		NP_001350624.1
PPT1	NM_001142604.2 link	c.125-3010T>G	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.125-15T>G		intron_variant	Intron 1 of 8		NM_000310.4	ENSP00000493153.1		P50897-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251398

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414570

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

706770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32420

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39442

South Asian (SAS)

AF:

0.00

AC:

AN:

85204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069120

Other (OTH)

AF:

0.0000170

AC:

AN:

58798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

- -

not provided

Pathogenic:1

Aug 08, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, with the c.125-15T>G variant causing aberrant splicing and reducing PPT1 enzyme activity (Bonsignore et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28957316, 19302939, 21990111, 16759889, 23374165) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.7

(source)

DANN

Benign

0.57

PhyloP100

0.97

Mutation Taster

=27/73

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.32

Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over