Variant 1-40089411-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000310.4(PPT1):c.535C>A(p.Arg179Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense, splice_region

Scores

Splicing: ADA: 0.0002399

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.99

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 Uncertain_significance. Variant got 4 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPT1	NM_000310.4 linkuse as main transcript	c.535C>A	p.Arg179Ser	missense_variant, splice_region_variant	5/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2 linkuse as main transcript	c.535C>A	p.Arg179Ser	missense_variant, splice_region_variant	5/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.226C>A	p.Arg76Ser	missense_variant, splice_region_variant	2/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.535C>A	p.Arg179Ser	missense_variant, splice_region_variant	5/9		NM_000310.4	ENSP00000493153	P1	P50897-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460420

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726630

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.61

D;.;.;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.15

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;D;D

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.48

T;T;T;T;T;T

MetaSVM

Uncertain

0.013

MutationAssessor

Benign

1.3

L;.;.;.;.;.

MutationTaster

Benign

0.67

D;D

PrimateAI

Benign

0.29

PROVEAN

Benign

0.26

.;.;.;.;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.56

.;.;.;.;.;T

Sift4G

Benign

0.67

.;.;.;.;.;T

Polyphen

0.0010

B;.;.;.;.;B

Vest4

0.51

MutPred

0.78

Gain of methylation at K174 (P = 0.0955);.;.;Gain of methylation at K174 (P = 0.0955);Gain of methylation at K174 (P = 0.0955);.;

MVP

0.92

MPC

0.14

ClinPred

0.28

GERP RS

2.9

Varity_R

0.25

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over