NM_000391.4:c.829G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000391.4(TPP1):c.829G>A(p.Val277Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,122 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V277V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.63

Publications

5 publications found

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 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

TPP1 links:

ENSG00000285338 (HGNC:):

ENSG00000285338 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000391.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 11-6616718-C-T is Pathogenic according to our data. Variant chr11-6616718-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 68749.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 link	c.829G>A	p.Val277Met	missense_variant	Exon 7 of 13	ENST00000299427.12	NP_000382.3	O14773-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 link	c.829G>A	p.Val277Met	missense_variant	Exon 7 of 13	1	NM_000391.4	ENSP00000299427.6		O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis

Pathogenic:1

Oct 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TPP1 c.829G>A (p.Val277Met) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, structural studies predicted this variant as destabilization of alpha 8 and might affect active site (Pal_2009, Guhaniyogi_2009). The variant was absent in 251454 control chromosomes (gnomAD). c.829G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Ju_2002, Sleat_2016). These data indicate that the variant may be associated with disease. At least one functional study reports this variant showed no measurable TPPI activity (Walus_2010). Additionally, missense variants in nearby residues (L275P, D276V, Q278R, Q278Q) have been reported in the Human Gene Mutation Database in association with Neuronal ceroid lipofuscinosis, supporting the functional importance of this region of the protein. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Neuronal ceroid lipofuscinosis 2

Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

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

PhyloP100

4.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.013

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.85

Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;

MVP

0.98

MPC

0.74

ClinPred

0.88

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.75

Mutation Taster

=18/82

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over