NM_001330588.2:c.673A>G

Variant names:

• chr13-102622929-A-G
• rs145635131
• NM_001330588.2:c.673A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001330588.2(TPP2):​c.673A>G​(p.Arg225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,614,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: TPP2 NM_001330588.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0119229555).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000112 (17/152314) while in subpopulation SAS AF = 0.00124 (6/4832). AF 95% confidence interval is 0.000541. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	NM_001330588.2	MANE Select	c.673A>G	p.Arg225Gly	missense	Exon 6 of 30	NP_001317517.1	Q5VZU9
	TPP2	NM_001367947.1		c.673A>G	p.Arg225Gly	missense	Exon 6 of 30	NP_001354876.1
	TPP2	NM_003291.4		c.673A>G	p.Arg225Gly	missense	Exon 6 of 29	NP_003282.2	P29144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP2	ENST00000376052.5	TSL:5 MANE Select	c.673A>G	p.Arg225Gly	missense	Exon 6 of 30	ENSP00000365220.3	Q5VZU9
	TPP2	ENST00000376065.8	TSL:1	c.673A>G	p.Arg225Gly	missense	Exon 6 of 29	ENSP00000365233.4	P29144
	TPP2	ENST00000912746.1		c.673A>G	p.Arg225Gly	missense	Exon 6 of 31	ENSP00000582805.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000342 AC: 86 AN: 251396 AF XY: 0.000471

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000212 AC: 310 AN: 1461840 Hom.: 1 Cov.: 29 AF XY: 0.000272 AC XY: 198 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1112000

Other (OTH) AF: 0.000232 AC: 14 AN: 60390

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74492

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.47
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.20	N
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.10
MPC		0.89
ClinPred		0.054	T
GERP RS		6.0
Varity_R		0.098
gMVP		0.60
Mutation Taster		=79/21	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: rs145635131; hg19: chr13-103275279;