rs121908197

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000391.4(TPP1):c.1027G>A(p.Glu343Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,744 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. E343D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 7.47

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 links:

ENSG00000285338 (HGNC:):

ENSG00000285338 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-6616361-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 11-6616363-C-T is Pathogenic according to our data. Variant chr11-6616363-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616363-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4 link	c.1027G>A	p.Glu343Lys	missense_variant	Exon 8 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.1027G>A	p.Glu343Lys	missense_variant	Exon 8 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251446

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135896

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:

0.000786

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000655

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 343 of the TPP1 protein (p.Glu343Lys). This variant is present in population databases (rs121908197, gnomAD 0.09%). This missense change has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (PMID: 10330339). ClinVar contains an entry for this variant (Variation ID: 68734). 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%. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). This variant disrupts the p.Glu343 amino acid residue in TPP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26224725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Dec 12, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TPP1 c.1027G>A (p.Glu343Lys) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251446 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (7.6e-05 vs 0.002), allowing no conclusion about variant significance. c.1027G>A has been reported in the literature in homozygous or compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Sleat_1999) or epilepsy (Truty_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent enzyme activity in transfected CHO cells (Walus_2010). The following publications have been ascertained in the context of this evaluation (PMID: 10330339, 31440721, 20340139). ClinVar contains an entry for this variant (Variation ID: 68734). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Neuronal ceroid lipofuscinosis 2

Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;.;D;.;.;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

D;D;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;.;.;.;.

Sift4G

Uncertain

0.042

D;T;.;.;.;.

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.95

MutPred

0.87

Gain of MoRF binding (P = 0.0031);.;.;.;.;.;

MVP

0.99

MPC

0.80

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.77

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over