rs786204753

Positions:

• chr11-6615217-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000391.4(TPP1):​c.1379G>A​(p.Trp460Ter) variant causes a stop gained 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPP1 NM_000391.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.30

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6615217-C-T is Pathogenic according to our data. Variant chr11-6615217-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6615217-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.1379G>A	p.Trp460Ter	stop_gained	11/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.1379G>A	p.Trp460Ter	stop_gained	11/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2012	p.Trp460Stop (TGG>TAG): c.1379 G>A in exon 11 of the TPP1 gene (NM_000391.3) The Trp460Stop nonsense mutation in the TPP1 gene has been reported previously in association with neuronal ceroid lipofuscinosis (NCL) (Sleat et al., 1997; Zhong et al., 2000). This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in CHILD-EPI panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2021	This premature translational stop signal has been observed in individual(s) with late-infantile neuronal ceroid lipofuscinosis (PMID: 11339651). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 189179). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp460*) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). -

Neuronal ceroid lipofuscinosis 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 11, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 24, 2021	- -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.93
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs786204753; hg19: chr11-6636448;