11-6617687-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_000391.4(TPP1):c.319G>A(p.Gly107Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G107G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.31

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

BP6

Variant 11-6617687-C-T is Benign according to our data. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568. Variant chr11-6617687-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 207568.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4 link	c.319G>A	p.Gly107Arg	missense_variant	Exon 4 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.319G>A	p.Gly107Arg	missense_variant	Exon 4 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251478

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000335

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1112012

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000652

AC:

AN:

41430

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000718

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 12, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a variant of uncertain significance in a patient with blindness in the literature, however additional clinical information was not provided and it is not known if this patient harbored a second TPP1 variant (PMID: 32483926); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32483926) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2

Uncertain:1

Oct 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis 2

Uncertain:1

Apr 14, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.6

H;.

PhyloP100

6.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.4

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.055

T;.

Polyphen

1.0

D;.

Vest4

0.79

MutPred

0.89

Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);

MVP

0.95

MPC

0.83

ClinPred

0.38

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.84

Mutation Taster

=201/99

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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