ENST00000533371.6:c.2T>C

Variant names:

• chr11-6616816-A-G
• rs1554901895
• ENST00000533371.6:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000533371.6(TPP1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,600 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPP1 ENST00000533371.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.78
• Publications: 1 publications found

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

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 38 codons. Genomic position: 6616706. Lost 0.116 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6616816-A-G is Pathogenic according to our data. Variant chr11-6616816-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 556877.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.731T>C	p.Met244Thr	missense_variant	Exon 7 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.731T>C	p.Met244Thr	missense_variant	Exon 7 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 244 of the TPP1 protein (p.Met244Thr). 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: 24091540). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556877). 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 Uncertain:1

Mar 01, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;.;D;.;T;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.
PhyloP100		8.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.4	N;N;.;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Benign	0.038	D;D;.;.;.;.;.
Sift4G	Benign	0.14	T;D;.;.;.;.;.
Polyphen		0.92	P;.;.;.;.;.;.
Vest4		0.90
MutPred		0.50		Gain of helix (P = 6e-04);.;.;.;Gain of helix (P = 6e-04);.;.;
MVP		0.99
MPC		0.78
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.86
Mutation Taster		=18/182	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

Other links and lift over

dbSNP: rs1554901895; hg19: chr11-6638047;