rs1800205

Positions:

chr1-40091361-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000310.4(PPT1):c.401T>C(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,613,744 control chromosomes in the GnomAD database, including 2,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 303 hom., cov: 31)

Exomes 𝑓: 0.052 ( 2661 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.689

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0022164583).

BP6

Variant 1-40091361-A-G is Benign according to our data. Variant chr1-40091361-A-G is described in ClinVar as [Benign]. Clinvar id is 130022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40091361-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PPT1	NM_000310.4 linkuse as main transcript	c.401T>C	p.Ile134Thr	missense_variant	4/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2 linkuse as main transcript	c.401T>C	p.Ile134Thr	missense_variant	4/8		NP_001350624.1
PPT1	NM_001142604.2 linkuse as main transcript	c.125-1849T>C		intron_variant			NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 linkuse as main transcript	c.401T>C	p.Ile134Thr	missense_variant	4/9		NM_000310.4	ENSP00000493153	P1	P50897-1

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7115

AN:

152088

Hom.:

303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0470

Gnomad OTH

AF:

0.0416

GnomAD3 exomes

AF:

0.0659

AC:

16560

AN:

251240

Hom.:

781

AF XY:

0.0698

AC XY:

9475

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00972

Gnomad AMR exome

AF:

0.0357

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.124

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.0483

Gnomad OTH exome

AF:

0.0579

GnomAD4 exome

AF:

0.0523

AC:

76456

AN:

1461538

Hom.:

2661

Cov.:

AF XY:

0.0548

AC XY:

39880

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00938

Gnomad4 AMR exome

AF:

0.0355

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.125

Gnomad4 SAS exome

AF:

0.118

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.0434

Gnomad4 OTH exome

AF:

0.0509

GnomAD4 genome

AF:

0.0468

AC:

7117

AN:

152206

Hom.:

303

Cov.:

AF XY:

0.0535

AC XY:

3980

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00963

Gnomad4 AMR

AF:

0.0351

Gnomad4 ASJ

AF:

0.0334

Gnomad4 EAS

AF:

0.123

Gnomad4 SAS

AF:

0.127

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.0470

Gnomad4 OTH

AF:

0.0412

Alfa

AF:

0.0475

Hom.:

350

Bravo

AF:

0.0366

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0474

AC:

408

ExAC

AF:

0.0661

AC:

8020

Asia WGS

AF:

0.122

AC:

421

AN:

3478

EpiCase

AF:

0.0447

EpiControl

AF:

0.0429

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Neuronal ceroid lipofuscinosis 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.62

D;.;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

.;D;D;D;D

MetaRNN

Benign

0.0022

T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.4

L;.;.;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.44

REVEL

Benign

0.20

Polyphen

0.015

B;.;.;.;.

MPC

0.16

ClinPred

0.00074

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.39

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