rs549928656

Positions:

chr11-6614927-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000391.4(TPP1):c.1490G>A(p.Arg497His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.0660

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047524244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.1490G>A	p.Arg497His	missense_variant	12/13	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.1490G>A	p.Arg497His	missense_variant	12/13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251466

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000447

Hom.:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 497 of the TPP1 protein (p.Arg497His). This variant is present in population databases (rs549928656, gnomAD 0.03%). 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: 457942). 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 not expected to disrupt TPP1 protein function. 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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 09, 2018	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

Neuronal ceroid lipofuscinosis 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.43

CADD

Benign

3.1

DANN

Benign

0.95

DEOGEN2

Uncertain

0.52

D;.;.;.;.;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.81

T;.;T;.;D;.;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.048

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

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.2

L;.;.;.;.;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-2.1

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

REVEL

Benign

0.19

Sift

Benign

0.12

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

Sift4G

Benign

0.12

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

Polyphen

0.0020

B;.;.;.;.;.;.

Vest4

0.039

MutPred

0.47

Loss of methylation at R497 (P = 0.0119);.;.;.;.;.;.;

MVP

0.67

MPC

0.24

ClinPred

0.032

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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