rs2300508

Variant names:

• chr21-18468278-C-T
• rs2300508
• NM_001428056.1:c.-173+17521G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001428056.1(TMPRSS15):​c.-173+17521G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 151,868 control chromosomes in the GnomAD database, including 16,860 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (16860 hom., cov: 32)
• Consequence: TMPRSS15 NM_001428056.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.818
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS15	NM_001428056.1	c.-173+17521G>A		intron_variant	Intron 1 of 28		NP_001414985.1
TMPRSS15	NM_001428057.1	c.-173+17521G>A		intron_variant	Intron 1 of 26		NP_001414986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS15	ENST00000422787.1	c.10+17521G>A		intron_variant	Intron 1 of 7	5		ENSP00000398253.1

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69441 AN: 151748 Hom.: 16845 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.458 AC: 69481 AN: 151868 Hom.: 16860 Cov.: 32 AF XY: 0.462 AC XY: 34273 AN XY: 74208

African (AFR) AF: 0.333 AC: 13801 AN: 41424

American (AMR) AF: 0.541 AC: 8238 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1724 AN: 3464

East Asian (EAS) AF: 0.909 AC: 4679 AN: 5150

South Asian (SAS) AF: 0.590 AC: 2844 AN: 4822

European-Finnish (FIN) AF: 0.462 AC: 4883 AN: 10562

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.466 AC: 31681 AN: 67914

Other (OTH) AF: 0.491 AC: 1032 AN: 2102

Alfa AF: 0.471 Hom.: 72561

Bravo AF: 0.461

Asia WGS AF: 0.720 AC: 2501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.37
DANN	Benign	0.26
PhyloP100		-0.82

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2300508; hg19: chr21-19840596;