rs1554901895

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000299427.12(TPP1):ā€‹c.731T>Cā€‹(p.Met244Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,600 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 Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TPP1
ENST00000299427.12 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.78
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPP1NM_000391.4 linkuse as main transcriptc.731T>C p.Met244Thr missense_variant 7/13 ENST00000299427.12 NP_000382.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPP1ENST00000299427.12 linkuse as main transcriptc.731T>C p.Met244Thr missense_variant 7/131 NM_000391.4 ENSP00000299427 P1O14773-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461600
Hom.:
0
Cov.:
41
AF XY:
0.00
AC XY:
0
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylMar 01, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T;.;.;.;.;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.86
D;.;D;.;T;.;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.9
L;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-2.4
N;N;.;.;.;.;.
REVEL
Pathogenic
0.87
Sift
Benign
0.038
D;D;.;.;.;.;.
Sift4G
Benign
0.14
T;D;.;.;.;.;.
Polyphen
0.92
P;.;.;.;.;.;.
Vest4
0.90
MutPred
0.50
Gain of helix (P = 6e-04);.;.;.;Gain of helix (P = 6e-04);.;.;
MVP
0.99
MPC
0.78
ClinPred
0.96
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.63
gMVP
0.86

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.

Other links and lift over

dbSNP: rs1554901895; hg19: chr11-6638047; API