rs2824721

Positions:

• chr21-18297801-G-T
• chr21-18297801-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002772.3(TMPRSS15):​c.2194C>A​(p.Pro732Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P732S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMPRSS15 NM_002772.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

Genes affected

TMPRSS15 (HGNC:9490): (transmembrane serine protease 15) This gene encodes an enzyme that converts the pancreatic proenzyme trypsinogen to trypsin, which activates other proenzymes including chymotrypsinogen and procarboxypeptidases. The precursor protein is cleaved into two chains that form a heterodimer linked by a disulfide bond. This protein is a member of the trypsin family of peptidases. Mutations in this gene cause enterokinase deficiency, a malabsorption disorder characterized by diarrhea and failure to thrive. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0852828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS15	NM_002772.3	c.2194C>A	p.Pro732Thr	missense_variant	19/25	ENST00000284885.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS15	ENST00000284885.8	c.2194C>A	p.Pro732Thr	missense_variant	19/25	1	NM_002772.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.9
DANN	Benign	0.30
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.15
Sift	Benign	0.51	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.49		Gain of glycosylation at P732 (P = 0.0466);
MVP		0.42
MPC		0.030
ClinPred		0.094	T
GERP RS		5.7
Varity_R		0.029
gMVP		0.29

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: rs2824721; hg19: chr21-19670118;