rs1128396

Positions:

chr11-6614875-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000391.4(TPP1):c.1542A>T(p.Gly514Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,522 control chromosomes in the GnomAD database, including 25,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2976 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22593 hom. )

Consequence

TPP1
NM_000391.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.208

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 11-6614875-T-A is Benign according to our data. Variant chr11-6614875-T-A is described in ClinVar as [Benign]. Clinvar id is 130608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6614875-T-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.208 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.1542A>T	p.Gly514Gly	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.1542A>T	p.Gly514Gly	synonymous_variant	12/13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29271

AN:

151578

Hom.:

2974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.203

GnomAD3 exomes

AF:

0.191

AC:

48076

AN:

251396

Hom.:

4950

AF XY:

0.190

AC XY:

25830

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.348

Gnomad SAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.172

AC:

251162

AN:

1461826

Hom.:

22593

Cov.:

AF XY:

0.172

AC XY:

125290

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.226

Gnomad4 AMR exome

AF:

0.180

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.341

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.140

Gnomad4 NFE exome

AF:

0.161

Gnomad4 OTH exome

AF:

0.191

GnomAD4 genome

AF:

0.193

AC:

29306

AN:

151696

Hom.:

2976

Cov.:

AF XY:

0.193

AC XY:

14314

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.247

Gnomad4 EAS

AF:

0.355

Gnomad4 SAS

AF:

0.198

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.167

Gnomad4 OTH

AF:

0.202

Alfa

AF:

0.177

Hom.:

794

Bravo

AF:

0.200

Asia WGS

AF:

0.245

AC:

853

AN:

3478

EpiCase

AF:

0.172

EpiControl

AF:

0.173

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2016	Variant summary: The TPP1 c.1542A>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 3/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. However, these predictions are not confirmed by experimental studies. This variant was found in 23452/121346 control chromosomes from the large and broad populations of ExAC (including 2381 homozygotes) at a frequency of 0.1932655, which is about 65 times greater than the maximal expected frequency of a pathogenic Tpp1 allele (0.002958). Therefore, the variant is a common benign polymorphism. It has been classified as likely benign by one laboratory before the ExAC control database was commonly used. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

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	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive spinocerebellar ataxia 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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

-0.41

CADD

Benign

6.2

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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