rs200880556

Positions:

chr11-6614574-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000391.4(TPP1):c.1664C>A(p.Ala555Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 1.07

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:

TPP1 (HGNC:):

TPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31289575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.1664C>A	p.Ala555Asp	missense_variant	13/13	ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.1664C>A	p.Ala555Asp	missense_variant	13/13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251454

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135900

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:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 555 of the TPP1 protein (p.Ala555Asp). This variant is present in population databases (rs200880556, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207597). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2018	p.Ala555Asp (GCT>GAT): c.1664 C>A in exon 13 of the TPP1 gene (NM_000391.3)The Ala555Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ala555Asp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged, non-polar Alanine residue is replaced by a negatively charged Aspartic acid residue. However, it alters a position in the protein that is not conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala555Asp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s). -

Neuronal ceroid lipofuscinosis 2

Uncertain:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Uncertain significance and reported on 03-09-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.41

T;.;.;.;.;.;.

Eigen

Benign

-0.012

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

T;.;T;.;T;.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.31

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

1.9

M;.;.;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.8

N;N;.;.;.;.;.

REVEL

Uncertain

0.48

Sift

Benign

0.13

T;T;.;.;.;.;.

Sift4G

Benign

0.50

T;T;.;.;.;.;.

Polyphen

0.85

P;.;.;.;.;.;.

Vest4

0.27

MVP

0.97

MPC

0.29

ClinPred

0.18

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.82

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

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