Variant rs386833669 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000310.4(PPT1):c.886T>C(p.Trp296Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.07

Variant links:

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]

PPT1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.93

PP5

Variant 1-40074096-A-G is Pathogenic according to our data. Variant chr1-40074096-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56218.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-40074096-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPT1	NM_000310.4 linkuse as main transcript	c.886T>C	p.Trp296Arg	missense_variant	9/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2 linkuse as main transcript	c.814T>C	p.Trp272Arg	missense_variant	8/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.577T>C	p.Trp193Arg	missense_variant	6/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.886T>C	p.Trp296Arg	missense_variant	9/9		NM_000310.4	ENSP00000493153	P1	P50897-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

0.90

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;.;.;.;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

.;T;T;T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

H;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-12

.;.;D;.;.;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.025

.;.;D;.;.;D

Sift4G

Pathogenic

0.0

.;.;D;.;.;D

Polyphen

0.95

P;.;.;.;.;D

Vest4

0.93, 0.87

MutPred

0.72

Gain of disorder (P = 0.0084);.;.;.;.;.;

MVP

1.0

MPC

0.77

ClinPred

1.0

GERP RS

5.8

Varity_R

0.99

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over