1-40097238-T-G

Variant names:

• chr1-40097238-T-G
• NM_000310.4:c.1A>C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000310.4(PPT1):​c.1A>C​(p.Met1?) variant causes a initiator codon 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.12

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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 23 pathogenic variants. Next in-frame start position is after 41 codons. Genomic position: 40097118. Lost 0.131 part of the original CDS.
• PS1: Another start lost variant in NM_000310.4 (PPT1) was described as [Likely_pathogenic] in ClinVar as 56193
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40097238-T-G is Pathogenic according to our data. Variant chr1-40097238-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2035352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 8		NP_001350624.1
PPT1	NM_001142604.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:2

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters PPT1 gene expression (PMID: 11440996). Disruption of the initiator codon has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11440996). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PPT1 mRNA. The next in-frame methionine is located at codon 41. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;.;.;.;.;.;T
Eigen	Benign	0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
PROVEAN	Benign	-0.42	.;.;N;.;.;N;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;.;D;.;.;D;D
Sift4G	Benign	0.27	.;.;T;.;.;D;.
Polyphen		0.27	B;.;.;.;.;P;.
Vest4		0.95, 0.95
MutPred		0.56		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.94
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-40562910;