chr13-102616412-A-T

Variant names:

• chr13-102616412-A-T
• rs1555298003
• NM_001330588.2:c.407A>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.407A>T​(p.Lys136Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,144 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. K136E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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, 0.77

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.407A>T	p.Lys136Ile	missense	Exon 4 of 30	NP_001317517.1
	TPP2	NM_001367947.1		c.407A>T	p.Lys136Ile	missense	Exon 4 of 30	NP_001354876.1
	TPP2	NM_003291.4		c.407A>T	p.Lys136Ile	missense	Exon 4 of 29	NP_003282.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	ENST00000376052.5	TSL:5 MANE Select	c.407A>T	p.Lys136Ile	missense	Exon 4 of 30	ENSP00000365220.3
	TPP2	ENST00000376065.8	TSL:1	c.407A>T	p.Lys136Ile	missense	Exon 4 of 29	ENSP00000365233.4
	TPP2	ENST00000912746.1		c.407A>T	p.Lys136Ile	missense	Exon 4 of 31	ENSP00000582805.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458144 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725304

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110840

Other (OTH) AF: 0.00 AC: 0 AN: 60236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.45
Sift	Benign	0.059	T
Sift4G	Benign	0.061	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.54		Loss of methylation at K136 (P = 0.0095)
MVP		0.21
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.61
gMVP		0.90
Mutation Taster		=25/75	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: rs1555298003; hg19: chr13-103268762;