21-18341504-C-T

Variant names:

• chr21-18341504-C-T
• rs2824751
• NM_002772.3:c.1473G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002772.3(TMPRSS15):​c.1473G>A​(p.Ala491Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,480 control chromosomes in the GnomAD database, including 46,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A491A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3733 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42773 hom.)
• Consequence: TMPRSS15 NM_002772.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.794
• Publications: 13 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 21-18341504-C-T is Benign according to our data. Variant chr21-18341504-C-T is described in ClinVar as Benign. ClinVar VariationId is 2008136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.794 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002772.3. 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
	TMPRSS15	NM_002772.3	MANE Select	c.1473G>A	p.Ala491Ala	synonymous	Exon 13 of 25	NP_002763.3	P98073
	TMPRSS15	NM_001428056.1		c.1608G>A	p.Ala536Ala	synonymous	Exon 17 of 29	NP_001414985.1
	TMPRSS15	NM_001428057.1		c.1473G>A	p.Ala491Ala	synonymous	Exon 15 of 27	NP_001414986.1	P98073

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS15	ENST00000284885.8	TSL:1 MANE Select	c.1473G>A	p.Ala491Ala	synonymous	Exon 13 of 25	ENSP00000284885.3	P98073

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32696 AN: 151972 Hom.: 3732 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.222 AC: 55886 AN: 251402 AF XY: 0.228

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.239 AC: 349559 AN: 1461390 Hom.: 42773 Cov.: 34 AF XY: 0.241 AC XY: 174902 AN XY: 727068

African (AFR) AF: 0.162 AC: 5432 AN: 33472

American (AMR) AF: 0.157 AC: 7039 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 7156 AN: 26130

East Asian (EAS) AF: 0.103 AC: 4072 AN: 39700

South Asian (SAS) AF: 0.256 AC: 22054 AN: 86252

European-Finnish (FIN) AF: 0.267 AC: 14282 AN: 53416

Middle Eastern (MID) AF: 0.230 AC: 1327 AN: 5766

European-Non Finnish (NFE) AF: 0.247 AC: 274197 AN: 1111554

Other (OTH) AF: 0.232 AC: 14000 AN: 60376

GnomAD4 genome AF: 0.215 AC: 32706 AN: 152090 Hom.: 3733 Cov.: 32 AF XY: 0.217 AC XY: 16108 AN XY: 74372

African (AFR) AF: 0.162 AC: 6728 AN: 41478

American (AMR) AF: 0.176 AC: 2690 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 944 AN: 3468

East Asian (EAS) AF: 0.110 AC: 570 AN: 5186

South Asian (SAS) AF: 0.254 AC: 1224 AN: 4818

European-Finnish (FIN) AF: 0.267 AC: 2829 AN: 10590

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16916 AN: 67952

Other (OTH) AF: 0.216 AC: 456 AN: 2110

Alfa AF: 0.230 Hom.: 8011

Bravo AF: 0.206

EpiCase AF: 0.251

EpiControl AF: 0.245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.2
DANN	Benign	0.31
PhyloP100		-0.79
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2824751; hg19: chr21-19713821; COSMIC: COSV53047234;