21-18297801-G-T

Variant names:

• chr21-18297801-G-T
• rs2824721
• NM_002772.3:c.2194C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000284885.8(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. 16/22 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 ENST00000284885.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28
• Publications: 36 publications found

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]

TMPRSS15 Gene-Disease associations (from GenCC):

• congenital enteropathy due to enteropeptidase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000284885.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS15	NM_002772.3	MANE Select	c.2194C>A	p.Pro732Thr	missense	Exon 19 of 25	NP_002763.3
	TMPRSS15	NM_001428056.1		c.2329C>A	p.Pro777Thr	missense	Exon 23 of 29	NP_001414985.1
	TMPRSS15	NM_001428057.1		c.2194C>A	p.Pro732Thr	missense	Exon 21 of 27	NP_001414986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS15	ENST00000284885.8	TSL:1 MANE Select	c.2194C>A	p.Pro732Thr	missense	Exon 19 of 25	ENSP00000284885.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.3
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
Mutation Taster		=94/6	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: rs2824721; hg19: chr21-19670118;