1-40092485-T-G

Position:

• chr1-40092485-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000310.4(PPT1):​c.147A>C​(p.Leu49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L49L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.144

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18799037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.147A>C	p.Leu49Phe	missense_variant	2/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.147A>C	p.Leu49Phe	missense_variant	2/8		NP_001350624.1
PPT1	NM_001142604.2	c.125-2973A>C		intron_variant			NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.147A>C	p.Leu49Phe	missense_variant	2/9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460984 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the PPT1 protein (p.Leu49Phe). This variant is present in population databases (rs781048683, gnomAD 0.0009%). 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: 533952). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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	0.10
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Uncertain	0.54	D;.;.;.;.;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.83	.;T;T;T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.89	L;.;.;.;.;.
PrimateAI	Benign	0.37	T
REVEL	Benign	0.27
Polyphen		0.0	B;.;.;.;.;.
MutPred		0.38		Loss of helix (P = 0.0626);.;.;Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.81
MPC		0.14
ClinPred		0.014	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.46

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

Other links and lift over

dbSNP: rs781048683; hg19: chr1-40558157;