1-40097125-C-A

Position:

• chr1-40097125-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000310.4(PPT1):​c.114G>T​(p.Trp38Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W38S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-40097125-C-A is Pathogenic according to our data. Variant chr1-40097125-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56144.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-40097125-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.114G>T	p.Trp38Cys	missense_variant	1/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.114G>T	p.Trp38Cys	missense_variant	1/8		NP_001350624.1
PPT1	NM_001142604.2	c.114G>T	p.Trp38Cys	missense_variant	1/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.114G>T	p.Trp38Cys	missense_variant	1/9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 16, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-12	.;.;D;.;.;N;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;.;.;T;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;T;.
Polyphen		1.0	D;.;.;.;.;P;.
Vest4		0.93, 0.83
MutPred		0.88		Loss of stability (P = 0.217);Loss of stability (P = 0.217);Loss of stability (P = 0.217);Loss of stability (P = 0.217);Loss of stability (P = 0.217);Loss of stability (P = 0.217);Loss of stability (P = 0.217);
MVP		0.94
MPC		0.73
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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

Other links and lift over

dbSNP: rs386833626; hg19: chr1-40562797;