rs201933080

Positions:

• chr13-102648955-C-G
• chr13-102648955-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001330588.2(TPP2):​c.2677C>G​(p.Arg893Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R893C) 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TPP2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP2	NM_001330588.2	c.2677C>G	p.Arg893Gly	missense_variant	22/30	ENST00000376052.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP2	ENST00000376052.5	c.2677C>G	p.Arg893Gly	missense_variant	22/30	5	NM_001330588.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460012 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.61		Gain of catalytic residue at I892 (P = 0.0051);Gain of catalytic residue at I892 (P = 0.0051);
MVP		0.34
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs201933080; hg19: chr13-103301305; COSMIC: COSV65752323; COSMIC: COSV65752323;