chr21-18343504-A-C

Variant names:

• chr21-18343504-A-C
• rs138221037
• NM_002772.3:c.1428+2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_002772.3(TMPRSS15):​c.1428+2T>G variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000468 in 1,606,144 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: TMPRSS15 NM_002772.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.06

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000483 (702/1453824) while in subpopulation AMR AF = 0.00224 (100/44620). AF 95% confidence interval is 0.00189. There are 3 homozygotes in GnomAdExome4. There are 315 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS15	NM_002772.3	c.1428+2T>G		splice_donor_variant, intron_variant	Intron 12 of 24	ENST00000284885.8	NP_002763.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS15	ENST00000284885.8	c.1428+2T>G		splice_donor_variant, intron_variant	Intron 12 of 24	1	NM_002772.3	ENSP00000284885.3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000548 AC: 137 AN: 249954 AF XY: 0.000414

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.000483 AC: 702 AN: 1453824 Hom.: 3 Cov.: 30 AF XY: 0.000435 AC XY: 315 AN XY: 723704

African (AFR) AF: 0.000120 AC: 4 AN: 33306

American (AMR) AF: 0.00224 AC: 100 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.000504 AC: 557 AN: 1105490

Other (OTH) AF: 0.000682 AC: 41 AN: 60126

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74482

African (AFR) AF: 0.000192 AC: 8 AN: 41580

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000393

ExAC AF: 0.000700 AC: 85

EpiCase AF: 0.000382

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Enterokinase deficiency Uncertain:1

Jun 19, 2023

Mendelics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 12 of the TMPRSS15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMPRSS15 are known to be pathogenic (PMID: 11719902). This variant is present in population databases (rs138221037, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TMPRSS15-related conditions. ClinVar contains an entry for this variant (Variation ID: 202209). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.1
GERP RS		5.2
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138221037; hg19: chr21-19715821;