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chr11-6616056-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000391.4(TPP1):​c.1094G>A​(p.Cys365Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000867 in 1,614,082 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C365R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.56
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-6616057-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 11-6616056-C-T is Pathogenic according to our data. Variant chr11-6616056-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616056-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TPP1NM_000391.4 linkuse as main transcriptc.1094G>A p.Cys365Tyr missense_variant 9/13 ENST00000299427.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TPP1ENST00000299427.12 linkuse as main transcriptc.1094G>A p.Cys365Tyr missense_variant 9/131 NM_000391.4 P1O14773-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251456
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000910
AC:
133
AN:
1461872
Hom.:
0
Cov.:
31
AF XY:
0.0000798
AC XY:
58
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000112
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000481
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 10, 2022Published functional studies have shown a decrease in TPP1 protease activity in the fibroblasts of affected patients (Sleat et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25326635, 19038966, 19038967, 10330339, 21990111, 19246452, 9788728, 29655203, 32146219, 32329550, 31283065, 31589614, 33268510, 26822727, 23042927, 26075876, 30771299, 9295267) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 27, 2024This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 365 of the TPP1 protein (p.Cys365Tyr). This variant is present in population databases (rs119455954, gnomAD 0.004%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 9788728, 10330339, 26075876). This variant is also known as c.4655G>A and c.1107T>C. ClinVar contains an entry for this variant (Variation ID: 2642). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Neuronal ceroid lipofuscinosis 2 Pathogenic:3Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 19, 1997- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 01, 2017This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: with W366X in a 7-year-old male with developmental delay/regression, hypertonia/spasticity, seizure, ataxia, myoclonus, progressive brain atrophy, vision loss; with c.509-1G>C in a 5-year-old male with developmental regression, truncal ataxia, seizure disorder, optic atrophy, diffuse brain atrophy. Heterozygotes are expected to be asymptomatic carriers. -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Likely pathogenic, criteria provided, single submitterliterature onlyCounsylJun 26, 2014- -
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 27, 2022- -
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 30, 2016Variant summary: The TPP1 c.1094G>A (p.Cys365Tyr) variant located in the Peptidase S8/S53 domain (via InterPro) causes a missense change involving the alteration of a Cysteine, which has been implicated to play a key role in disulfide linkages needed to stabilize the fold (Guhaniyogi_2009 (PMID: 19038967). In addition, 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121330 (1/60665), which does not exceed the estimated maximal expected allele frequency for a pathogenic TPP1 variant of 1/338. Multiple publications cite individuals affected with Late-Infantile Neuronal Ceroid-Lipofuscinoses, who are homozygous or compound heterozygous for the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic" or "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;.;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D;.;D;.;D;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.4
H;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-9.0
D;D;.;.;.;.;.
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0020
D;D;.;.;.;.;.
Sift4G
Uncertain
0.0040
D;D;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.94
MVP
1.0
MPC
0.99
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs119455954; hg19: chr11-6637287; API