rs769874271

Variant names:

• chr13-102640299-C-A
• rs769874271
• NM_001330588.2:c.1943C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-102640299-C-A
• chr13-102640299-C-G
• chr13-102640299-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001330588.2(TPP2):​c.1943C>A​(p.Ala648Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,810 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A648G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.48
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12915906).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000206 (30/1459758) while in subpopulation AMR AF = 0.000313 (14/44692). AF 95% confidence interval is 0.000189. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	NM_001330588.2	MANE Select	c.1943C>A	p.Ala648Asp	missense	Exon 16 of 30	NP_001317517.1
	TPP2	NM_001367947.1		c.1943C>A	p.Ala648Asp	missense	Exon 16 of 30	NP_001354876.1
	TPP2	NM_003291.4		c.1943C>A	p.Ala648Asp	missense	Exon 16 of 29	NP_003282.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	ENST00000376052.5	TSL:5 MANE Select	c.1943C>A	p.Ala648Asp	missense	Exon 16 of 30	ENSP00000365220.3
	TPP2	ENST00000376065.8	TSL:1	c.1943C>A	p.Ala648Asp	missense	Exon 16 of 29	ENSP00000365233.4
	TPP2	ENST00000651544.1		c.1931C>A	p.Ala644Asp	missense	Exon 16 of 27	ENSP00000498728.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250948 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

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: 0.0000206 AC: 30 AN: 1459758 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 726168

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.000313 AC: 14 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110584

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4

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

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 648 of the TPP2 protein (p.Ala648Asp). This variant is present in population databases (rs769874271, gnomAD 0.04%). 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: 1040059). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.060
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.12
Sift	Benign	0.40	T
Sift4G	Benign	0.37	T
Polyphen		0.029	B
Vest4		0.45
MutPred		0.47		Gain of disorder (P = 0.0561)
MVP		0.38
MPC		1.0
ClinPred		0.062	T
GERP RS		5.0
Varity_R		0.20
gMVP		0.48
Mutation Taster		=85/15	polymorphism

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: rs769874271; hg19: chr13-103292649;