11-6616033-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000391.4(TPP1):c.1117C>G(p.Gln373Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,168 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 6 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.26

Publications

5 publications found

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 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

TPP1 links:

ENSG00000285338 (HGNC:):

ENSG00000285338 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070130825).

BP6

Variant 11-6616033-G-C is Benign according to our data. Variant chr11-6616033-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 137701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00745 (1135/152294) while in subpopulation AFR AF = 0.0258 (1071/41548). AF 95% confidence interval is 0.0245. There are 14 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4 link	c.1117C>G	p.Gln373Glu	missense_variant	Exon 9 of 13	ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 link	c.1117C>G	p.Gln373Glu	missense_variant	Exon 9 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00743

AC:

1131

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00765

GnomAD2 exomes

AF:

0.00207

AC:

520

AN:

251458

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000850

AC:

1242

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

543

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0274

AC:

918

AN:

33480

American (AMR)

AF:

0.00195

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1112008

Other (OTH)

AF:

0.00215

AC:

130

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00745

AC:

1135

AN:

152294

Hom.:

Cov.:

AF XY:

0.00718

AC XY:

535

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0258

AC:

1071

AN:

41548

American (AMR)

AF:

0.00236

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68030

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000873

Hom.:

Bravo

AF:

0.00866

ESP6500AA

AF:

0.0254

AC:

112

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00249

AC:

302

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 20, 2018

Athena Diagnostics

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis 2

Benign:3

Nov 23, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 26, 2013

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. -

Inborn genetic diseases

Benign:1

Jan 08, 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

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.26

T;.;.;.;.;.;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.84

T;.;T;.;T;.;T

MetaRNN

Benign

0.0070

T;T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.84

L;.;.;.;.;.;.

PhyloP100

1.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.62

N;N;.;.;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.73

T;T;.;.;.;.;.

Sift4G

Benign

0.79

T;T;.;.;.;.;.

Polyphen

0.012

B;.;.;.;.;.;.

Vest4

0.34

MVP

0.85

MPC

0.21

ClinPred

0.0018

GERP RS

0.79

Varity_R

0.12

gMVP

0.69

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-6616033-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over