13-102640299-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330588.2(TPP2):​c.1943C>T​(p.Ala648Val) 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 1,459,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A648D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Ala648Val	missense	Exon 16 of 30	NP_001317517.1
	TPP2	NM_001367947.1		c.1943C>T	p.Ala648Val	missense	Exon 16 of 30	NP_001354876.1
	TPP2	NM_003291.4		c.1943C>T	p.Ala648Val	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>T	p.Ala648Val	missense	Exon 16 of 30	ENSP00000365220.3
	TPP2	ENST00000376065.8	TSL:1	c.1943C>T	p.Ala648Val	missense	Exon 16 of 29	ENSP00000365233.4
	TPP2	ENST00000651544.1		c.1931C>T	p.Ala644Val	missense	Exon 16 of 27	ENSP00000498728.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459758 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726168

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 53284

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110584

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.038
Sift	Benign	0.36	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.36		Gain of catalytic residue at D651 (P = 0.0019)
MVP		0.043
MPC		0.69
ClinPred		0.46	T
GERP RS		5.0
Varity_R		0.082
gMVP		0.22
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769874271; hg19: chr13-103292649;