13-102597130-C-T

Variant names:

• chr13-102597130-C-T
• rs375925353
• NM_001330588.2:c.92C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP3 BP4_Moderate BS1_Supporting

The NM_001330588.2(TPP2):​c.92C>T​(p.Pro31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,610,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.57
• Publications: 1 publications found

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

LOC107984588 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PrimateAI, PROVEAN [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.08692995).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000546 (83/152054) while in subpopulation AMR AF = 0.00366 (56/15298). AF 95% confidence interval is 0.00289. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP2	NM_001330588.2	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 30	ENST00000376052.5	NP_001317517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP2	ENST00000376052.5	c.92C>T	p.Pro31Leu	missense_variant	Exon 1 of 30	5	NM_001330588.2	ENSP00000365220.3

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151936 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

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: 0.000221

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000181 AC: 44 AN: 242710 AF XY: 0.000203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000760

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1458386 Hom.: 0 Cov.: 31 AF XY: 0.000119 AC XY: 86 AN XY: 725416

African (AFR) AF: 0.0000301 AC: 1 AN: 33230

American (AMR) AF: 0.000986 AC: 44 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85922

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4866

European-Non Finnish (NFE) AF: 0.0000999 AC: 111 AN: 1111020

Other (OTH) AF: 0.000382 AC: 23 AN: 60146

GnomAD4 genome AF: 0.000546 AC: 83 AN: 152054 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74358

African (AFR) AF: 0.000145 AC: 6 AN: 41490

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67922

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000918

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92C>T (p.P31L) alteration is located in exon 1 (coding exon 1) of the TPP2 gene. This alteration results from a C to T substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the TPP2 protein (p.Pro31Leu). This variant is present in population databases (rs375925353, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with TPP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 478057). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Uncertain	0.041	D
MutationAssessor	Pathogenic	3.2	M;.
PhyloP100		6.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.8	D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.81
MVP		0.38
MPC		1.8
ClinPred		0.86	D
GERP RS		3.9
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.88
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs375925353; hg19: chr13-103249480;