rs386833631

Positions:

• chr1-40092507-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000310.4(PPT1):​c.125G>A​(p.Gly42Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,452,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PPT1 NM_000310.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.55

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 Likely_pathogenic. Variant got 9 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, 0.988
• PP5: Variant 1-40092507-C-T is Pathogenic according to our data. Variant chr1-40092507-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56179.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr1-40092507-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.125G>A	p.Gly42Glu	missense_variant, splice_region_variant	2/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.125G>A	p.Gly42Glu	missense_variant, splice_region_variant	2/8		NP_001350624.1
PPT1	NM_001142604.2	c.125-2995G>A		intron_variant			NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.125G>A	p.Gly42Glu	missense_variant, splice_region_variant	2/9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1452024 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 722964

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: 0.00000816

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 28, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 42 of the PPT1 protein (p.Gly42Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56179). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

Neuronal ceroid lipofuscinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 13, 2023

Variant summary: PPT1 c.125G>A (p.Gly42Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site and two predict the variant weakens the 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251424 control chromosomes (gnomAD). c.125G>A has been reported in the literature as a compound heterozygous genotype in two siblings affected with infantile onset Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant may be associated with disease. Additionally, a functional study found the variant showed no detectable instrinsic enzyme activity in vitro, with <2% activity of the WT protein (Das_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11440996, 9664077, 10191107). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.35	.;T;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.9	.;.;.;.;D
Sift	Pathogenic	0.0	.;.;.;.;D
Polyphen		1.0	D;.;.;.;.
MutPred		0.96		Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833631; hg19: chr1-40558179;