NM_001330588.2:c.91C>T

Variant names:

• chr13-102597129-C-T
• rs1169336796
• NM_001330588.2:c.91C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001330588.2(TPP2):​c.91C>T​(p.Pro31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,546 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 (★). 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC107984588 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330588.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	NM_001330588.2	MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 1 of 30	NP_001317517.1	Q5VZU9
	TPP2	NM_001367947.1		c.91C>T	p.Pro31Ser	missense	Exon 1 of 30	NP_001354876.1
	TPP2	NM_003291.4		c.91C>T	p.Pro31Ser	missense	Exon 1 of 29	NP_003282.2	P29144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	ENST00000376052.5	TSL:5 MANE Select	c.91C>T	p.Pro31Ser	missense	Exon 1 of 30	ENSP00000365220.3	Q5VZU9
	TPP2	ENST00000376065.8	TSL:1	c.91C>T	p.Pro31Ser	missense	Exon 1 of 29	ENSP00000365233.4	P29144
	TPP2	ENST00000912746.1		c.91C>T	p.Pro31Ser	missense	Exon 1 of 31	ENSP00000582805.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458546 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725506

African (AFR) AF: 0.00 AC: 0 AN: 33240

American (AMR) AF: 0.0000224 AC: 1 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4872

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111102

Other (OTH) AF: 0.00 AC: 0 AN: 60158

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.57		Gain of catalytic residue at L27 (P = 0)
MVP		0.33
MPC		1.7
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		0.0096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.88
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1169336796; hg19: chr13-103249479;