rs150748717

chr13-102676288-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_001330588.2(TPP2):c.3580-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000774 in 1,584,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: TPP2 NM_001330588.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003193
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.760

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-102676288-C-T is Benign according to our data. Variant chr13-102676288-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 544317.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-102676288-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000716 (109/152258) while in subpopulation NFE AF= 0.00129 (88/67992). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP2	NM_001330588.2	c.3580-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000376052.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP2	ENST00000376052.5	c.3580-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330588.2	A1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000663 AC: 156 AN: 235146 Hom.: 1 AF XY: 0.000660 AC XY: 84 AN XY: 127204

Gnomad AFR exome AF: 0.000136

Gnomad AMR exome AF: 0.000530

Gnomad ASJ exome AF: 0.00373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000933

Gnomad OTH exome AF: 0.000521

GnomAD4 exome AF: 0.000780 AC: 1117 AN: 1432618 Hom.: 1 Cov.: 30 AF XY: 0.000738 AC XY: 526 AN XY: 712700

Gnomad4 AFR exome AF: 0.0000625

Gnomad4 AMR exome AF: 0.000596

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000836

Gnomad4 OTH exome AF: 0.000915

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74430

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.000676

Asia WGS AF: 0.000290 AC: 1 AN: 3462

ClinVar

Significance: Likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.3
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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: rs150748717; hg19: chr13-103328638;