rs1128396

chr11-6614875-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000391.4(TPP1):c.1542A>T(p.Gly514=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.208

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]

ACMG classification

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	UniProt
TPP1	NM_000391.4	c.1542A>T	p.Gly514=	synonymous_variant	12/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.1542A>T	p.Gly514=	synonymous_variant	12/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29271 AN: 151578 Hom.: 2974 Cov.: 32

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

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.: 34 AF XY: 0.172 AC XY: 125290 AN XY: 727220

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.: 32 AF XY: 0.193 AC XY: 14314 AN XY: 74136

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
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. -

Neuronal ceroid lipofuscinosis 2 Benign:5

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

not specified Benign:2

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. -

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

Other links and lift over

dbSNP: rs1128396; hg19: chr11-6636106; COSMIC: COSV54990948; COSMIC: COSV54990948;