rs117942457

Variant names:

• chr11-6614923-G-A
• rs117942457
• NM_000391.4:c.1494C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-6614923-G-A
• chr11-6614923-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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 (★★). Synonymous variant affecting the same amino acid position (i.e. P498P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (132 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.03
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, G2P, Orphanet
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.1494C>T	p.Pro498Pro	synonymous_variant	Exon 12 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.1494C>T	p.Pro498Pro	synonymous_variant	Exon 12 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1317 AN: 152108 Hom.: 6 Cov.: 32

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

GnomAD2 exomes AF: 0.00863 AC: 2169 AN: 251474 AF XY: 0.00833

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 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.: 33 AF XY: 0.0113 AC XY: 8225 AN XY: 727246

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.00394 AC: 176 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00161 AC: 64 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.0165 AC: 881 AN: 53410

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0139 AC: 15461 AN: 1112010

Other (OTH) AF: 0.00949 AC: 573 AN: 60396

GnomAD4 genome AF: 0.00865 AC: 1317 AN: 152226 Hom.: 6 Cov.: 32 AF XY: 0.00857 AC XY: 638 AN XY: 74436

African (AFR) AF: 0.00258 AC: 107 AN: 41526

American (AMR) AF: 0.00379 AC: 58 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0190 AC: 201 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 931 AN: 68018

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00956 Hom.: 8

Bravo AF: 0.00727

Asia WGS AF: 0.00115 AC: 4 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

Submissions by phenotype

not specified Benign:5

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 30, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Nov 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPP1: BP4, BP7, BS1, BS2 -

Neuronal ceroid lipofuscinosis 2 Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Jun 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs117942457; hg19: chr11-6636154;