rs117942457

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000391.4(TPP1):c.1494C>T(p.Pro498Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,108 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 6 hom., cov: 32)

Exomes 𝑓: 0.012 ( 132 hom. )

Consequence

TPP1
NM_000391.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.03

Variant links:

Genes affected

TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

TPP1 links:

TPP1 (HGNC:):

TPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 11-6614923-G-A is Benign according to our data. Variant chr11-6614923-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00865 (1317/152226) while in subpopulation NFE AF= 0.0137 (931/68018). AF 95% confidence interval is 0.013. There are 6 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.1494C>T	p.Pro498Pro	synonymous_variant	12/13	ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.1494C>T	p.Pro498Pro	synonymous_variant	12/13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00866

AC:

1317

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00863

AC:

2169

AN:

251474

Hom.:

AF XY:

0.00833

AC XY:

1132

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00364

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0135

Gnomad OTH exome

AF:

0.00879

GnomAD4 exome

AF:

0.0118

AC:

17285

AN:

1461882

Hom.:

132

Cov.:

AF XY:

0.0113

AC XY:

8225

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00394

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00161

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.00949

GnomAD4 genome

AF:

0.00865

AC:

1317

AN:

152226

Hom.:

Cov.:

AF XY:

0.00857

AC XY:

638

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00727

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2022	- -
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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TPP1: BP4, BP7, BS1, BS2 -

Neuronal ceroid lipofuscinosis 2

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 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

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.28

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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