rs73578896

chr13-102636248-G-Achr13-102636248-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001330588.2(TPP2):c.1534G>A(p.Val512Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,612,336 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (6 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TPP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0076164305).
• BP6: Variant 13-102636248-G-A is Benign according to our data. Variant chr13-102636248-G-A is described in ClinVar as [Benign]. Clinvar id is 544313.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00315 (479/151970) while in subpopulation AFR AF= 0.0111 (461/41456). AF 95% confidence interval is 0.0103. There are 4 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP2	NM_001330588.2	c.1534G>A	p.Val512Ile	missense_variant	13/30	ENST00000376052.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP2	ENST00000376052.5	c.1534G>A	p.Val512Ile	missense_variant	13/30	5	NM_001330588.2	A1

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 151852 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000740 AC: 185 AN: 250024 Hom.: 1 AF XY: 0.000547 AC XY: 74 AN XY: 135214

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000310 AC: 452 AN: 1460366 Hom.: 6 Cov.: 30 AF XY: 0.000266 AC XY: 193 AN XY: 726498

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.00315 AC: 479 AN: 151970 Hom.: 4 Cov.: 32 AF XY: 0.00310 AC XY: 230 AN XY: 74282

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000606 Hom.: 1

Bravo AF: 0.00347

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.28	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.13
Sift	Benign	0.43	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0020	B;.
Vest4		0.11
MVP		0.043
MPC		0.56
ClinPred		0.011	T
GERP RS		-0.030
Varity_R		0.017
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs73578896; hg19: chr13-103288598;