Genetic Variant TPP2:p.Cys28Gly (chr13-102597120-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001330588.2(TPP2):c.82T>G(p.Cys28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TPP2
NM_001330588.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.480

Publications

1 publications found

Variant links:

Genes affected

TPP2 (HGNC:12016): (tripeptidyl peptidase 2) This gene encodes a mammalian peptidase that, at neutral pH, removes tripeptides from the N terminus of longer peptides. The protein has a specialized function that is essential for some MHC class I antigen presentation. The protein is a high molecular mass serine exopeptidase; the amino acid sequence surrounding the serine residue at the active site is similar to the peptidases of the subtilisin class rather than the trypsin class. [provided by RefSeq, Jul 2008]

TPP2 Gene-Disease associations (from GenCC):

immunodeficiency 78 with autoimmunity and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPP2 links:

ENSG00000276957 (HGNC:):

ENSG00000276957 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09501982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP2	NM_001330588.2 link	c.82T>G	p.Cys28Gly	missense_variant	Exon 1 of 30	ENST00000376052.5	NP_001317517.1	P29144Q5VZU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP2	ENST00000376052.5 link	c.82T>G	p.Cys28Gly	missense_variant	Exon 1 of 30	5	NM_001330588.2	ENSP00000365220.3		Q5VZU9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458974

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33280

American (AMR)

AF:

0.00

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53086

Middle Eastern (MID)

AF:

0.000204

AC:

AN:

4894

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111238

Other (OTH)

AF:

0.00

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 10, 2021

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Immunodeficiency 78 with autoimmunity and developmental delay

Uncertain:1

Feb 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.088

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.095

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

PhyloP100

0.48

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.14

N;N

REVEL

Benign

0.019

Sift

Benign

0.40

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0

B;.

Vest4

0.31

MutPred

0.44

Gain of catalytic residue at L27 (P = 0.0031);Gain of catalytic residue at L27 (P = 0.0031);

MVP

0.068

MPC

0.85

ClinPred

0.10

GERP RS

3.0

PromoterAI

-0.0040

Neutral

(source)

Varity_R

0.22

gMVP

0.65

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over