11-6616690-T-C

Position:

• chr11-6616690-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000391.4(TPP1):​c.857A>G​(p.Asn286Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N286K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.55

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000391.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6616689-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527750.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 11-6616690-T-C is Pathogenic according to our data. Variant chr11-6616690-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616690-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.857A>G	p.Asn286Ser	missense_variant	7/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.857A>G	p.Asn286Ser	missense_variant	7/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

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: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2017	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPP1 function (PMID: 14736728, 15317752, 20340139). 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. ClinVar contains an entry for this variant (Variation ID: 2648). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 12376936, 30541466). This variant is present in population databases (rs119455958, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 286 of the TPP1 protein (p.Asn286Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D;.;D;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N;N;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;T;.;.;.;.;.
Sift4G	Benign	0.23	T;T;.;.;.;.;.
Polyphen		0.77	P;.;.;.;.;.;.
Vest4		0.92
MutPred		0.83		Gain of disorder (P = 0.097);.;.;.;Gain of disorder (P = 0.097);.;.;
MVP		0.94
MPC		0.37
ClinPred		0.85	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs119455958; hg19: chr11-6637921;