1-40074068-A-G

Variant names:

• chr1-40074068-A-G
• rs386833671
• NM_000310.4:c.914T>C

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.914T>C​(p.Leu305Pro) variant causes a missense change involving the alteration of a 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L305I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.46

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 90 pathogenic changes around while only 6 benign (94%) in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 1-40074068-A-G is Pathogenic according to our data. Variant chr1-40074068-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56220.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40074068-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.914T>C	p.Leu305Pro	missense_variant	Exon 9 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.842T>C	p.Leu281Pro	missense_variant	Exon 8 of 8		NP_001350624.1
PPT1	NM_001142604.2	c.605T>C	p.Leu202Pro	missense_variant	Exon 6 of 6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.914T>C	p.Leu305Pro	missense_variant	Exon 9 of 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:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.63	.;T;T;T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.0	.;.;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;D
Polyphen		1.0	D;.;.;.;.;D
Vest4		0.88, 0.67
MutPred		0.77		Loss of helix (P = 0.0068);.;.;.;.;.;
MVP		0.99
MPC		0.74
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.92

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: rs386833671; hg19: chr1-40539740;