rs2824721

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002772.3(TMPRSS15):​c.2194C>T​(p.Pro732Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 1,612,248 control chromosomes in the GnomAD database, including 480,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (42930 hom., cov: 31)
  • Exomes 𝑓: 0.77 (437723 hom.)
• Consequence: TMPRSS15 NM_002772.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.796112E-7).
• BP6: Variant 21-18297801-G-A is Benign according to our data. Variant chr21-18297801-G-A is described in ClinVar as [Benign]. Clinvar id is 1995943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS15	NM_002772.3	c.2194C>T	p.Pro732Ser	missense_variant	Exon 19 of 25	ENST00000284885.8	NP_002763.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS15	ENST00000284885.8	c.2194C>T	p.Pro732Ser	missense_variant	Exon 19 of 25	1	NM_002772.3	ENSP00000284885.3

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113950 AN: 151918 Hom.: 42889 Cov.: 31

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.751 AC: 188709 AN: 251242 AF XY: 0.753

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.694

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.790

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.773 AC: 1129173 AN: 1460212 Hom.: 437723 Cov.: 41 AF XY: 0.772 AC XY: 560693 AN XY: 726496

African (AFR) AF: 0.702 AC: 23461 AN: 33424

American (AMR) AF: 0.698 AC: 31222 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 19187 AN: 26106

East Asian (EAS) AF: 0.674 AC: 26704 AN: 39610

South Asian (SAS) AF: 0.717 AC: 61778 AN: 86218

European-Finnish (FIN) AF: 0.808 AC: 43139 AN: 53384

Middle Eastern (MID) AF: 0.723 AC: 4165 AN: 5760

European-Non Finnish (NFE) AF: 0.786 AC: 873180 AN: 1110684

Other (OTH) AF: 0.768 AC: 46337 AN: 60320

GnomAD4 genome AF: 0.750 AC: 114035 AN: 152036 Hom.: 42930 Cov.: 31 AF XY: 0.750 AC XY: 55736 AN XY: 74310

African (AFR) AF: 0.705 AC: 29224 AN: 41450

American (AMR) AF: 0.733 AC: 11195 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2509 AN: 3472

East Asian (EAS) AF: 0.662 AC: 3419 AN: 5164

South Asian (SAS) AF: 0.718 AC: 3449 AN: 4804

European-Finnish (FIN) AF: 0.808 AC: 8540 AN: 10568

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53372 AN: 67988

Other (OTH) AF: 0.746 AC: 1576 AN: 2112

Alfa AF: 0.768 Hom.: 146237

Bravo AF: 0.739

TwinsUK AF: 0.788 AC: 2922

ALSPAC AF: 0.778 AC: 2997

ESP6500AA AF: 0.705 AC: 3108

ESP6500EA AF: 0.783 AC: 6734

ExAC AF: 0.754 AC: 91567

Asia WGS AF: 0.700 AC: 2434 AN: 3478

EpiCase AF: 0.781

EpiControl AF: 0.775

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.0
DANN	Benign	0.11
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.00088	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.6	N
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.028
ClinPred		0.0043	T
GERP RS		5.7
Varity_R		0.022
gMVP		0.22
Mutation Taster		=87/13	polymorphism (auto)

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; COSMIC: COSV53034989;