rs386833627

Positions:

• chr1-40097122-A-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.117T>A​(p.His39Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.42

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 chain Palmitoyl-protein thioesterase 1 (size 278) in uniprot entity PPT1_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) 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 1-40097122-A-T is Pathogenic according to our data. Variant chr1-40097122-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56175.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40097122-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.117T>A	p.His39Gln	missense_variant	1/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.117T>A	p.His39Gln	missense_variant	1/8		NP_001350624.1
PPT1	NM_001142604.2	c.117T>A	p.His39Gln	missense_variant	1/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.117T>A	p.His39Gln	missense_variant	1/9		NM_000310.4	ENSP00000493153	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	.;T;D;D;D;T;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;H;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.4	.;.;D;.;.;N;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	.;.;D;.;.;T;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;T;.
Polyphen		1.0	D;.;.;.;.;P;.
Vest4		0.88, 0.85
MutPred		0.97		Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);Loss of catalytic residue at G40 (P = 0.1273);
MVP		0.97
MPC		0.58
ClinPred		1.0	D
GERP RS		-0.23
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs386833627; hg19: chr1-40562794;