NM_000391.4:c.1613C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000391.4(TPP1):​c.1613C>A​(p.Ser538Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S538C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TPP1
NM_000391.4 missense

Scores

8
10
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.35

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.882
PP5
Variant 11-6614625-G-T is Pathogenic according to our data. Variant chr11-6614625-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2136995.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPP1NM_000391.4 linkc.1613C>A p.Ser538Tyr missense_variant Exon 13 of 13 ENST00000299427.12 NP_000382.3 O14773-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPP1ENST00000299427.12 linkc.1613C>A p.Ser538Tyr missense_variant Exon 13 of 13 1 NM_000391.4 ENSP00000299427.6 O14773-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Aug 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 538 of the TPP1 protein (p.Ser538Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 26032578). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.;.;.;.;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;.;D;.;D;.;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M;.;.;.;.;.;.
PhyloP100
7.3
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.3
D;D;.;.;.;.;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0050
D;D;.;.;.;.;.
Sift4G
Uncertain
0.0020
D;D;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.70
MutPred
0.66
Loss of glycosylation at S538 (P = 0.0112);.;.;.;.;.;.;
MVP
0.98
MPC
0.73
ClinPred
0.98
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.57
gMVP
0.91
Mutation Taster
=17/83
disease causing

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

Other links and lift over

dbSNP: rs755878872; hg19: chr11-6635856; API