rs386833639

Variant names:

• chr1-40092135-T-A
• NM_000310.4:c.272A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40092135-T-A
• chr1-40092135-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000310.4(PPT1):​c.272A>T​(p.Gln91Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q91P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86

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 10 ACMG points.

• PM1: In a chain Palmitoyl-protein thioesterase 1 (size 278) in uniprot entity PPT1_HUMAN there are 91 pathogenic changes around while only 6 benign (94%) in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40092135-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56187.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 8		NP_001350624.1
PPT1	NM_001142604.2	c.125-2623A>T		intron_variant	Intron 1 of 5		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.272A>T	p.Gln91Leu	missense_variant	Exon 3 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
PrimateAI	Benign	0.45	T
REVEL	Pathogenic	0.95
Polyphen		1.0	D;.;.;.;.
MutPred		0.87		Loss of catalytic residue at Q91 (P = 0.0694);.;.;Loss of catalytic residue at Q91 (P = 0.0694);Loss of catalytic residue at Q91 (P = 0.0694);
MVP		0.98
MPC		0.57
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr1-40557807;