rs121908202

chr11-6615172-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000391.4(TPP1):c.1424C>T(p.Ser475Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S475S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TPP1 NM_000391.4 missense, splice_region
• Scores: Splicing: ADA: 0.9869
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.24

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000391.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-6615172-G-A is Pathogenic according to our data. Variant chr11-6615172-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6615172-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-6615172-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.1424C>T	p.Ser475Leu	missense_variant, splice_region_variant	11/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.1424C>T	p.Ser475Leu	missense_variant, splice_region_variant	11/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251484 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135916

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2017	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 13, 2023	A Homozygous missense variation in exon 11 of the TPP1 gene that results in the amino acid substitution of Leucine for Serine at codon 475 was detected. The observed variant c.1424C>T (p.Ser475Leu) has not been reported in the 1000 genomes and has a MAF of 0.0024% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, FATHMM and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2019	Published functional studies demonstrate that the S475L variant results in no measurable TPP1 activity compared to wild type (Walus et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31216804, 31283065, 31059981, 31139143, 25976102, 19246452, 15965709, 10477428, 11054422, 10330339, 19038966, 20340139, 21990111, 23266810) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 18, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPP1 function (PMID: 20340139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 68741). This missense change has been observed in individual(s) with TPP1-related conditions (PMID: 10330339, 21990111, 23266810). This variant is present in population databases (rs121908202, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 475 of the TPP1 protein (p.Ser475Leu). -

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 07, 2022

Variant summary: TPP1 c.1424C>T (p.Ser475Leu) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.4e-05 in 251484 control chromosomes (gnomAD). c.1424C>T has been reported in the literature as a biallelic genotype in individuals affected with Neuronal Ceroid-Lipofuscinosis (e.g. Sleat_1999, Dozieres-Puyravel_2020) and refractory epilepsy with intellectual disability (e.g. Long_2019). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating the variant in Chinese Hamster Ovary cells showed that the variant had no detectable enzymatic activity (0% of wild-type) despite normal translation, post translational processing, and trafficking (Walus_2010). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;.;D;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	4.6	H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D;D;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.98
MVP		1.0
MPC		0.71
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.81
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

Other links and lift over

dbSNP: rs121908202; hg19: chr11-6636403;