NM_002772.3:c.151_155delGCACT

Variant names:

• chr21-18398319-AAGTGC-A
• rs1555909961
• NM_002772.3:c.151_155delGCACT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002772.3(TMPRSS15):​c.151_155delGCACT​(p.Ala51TrpfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS15 NM_002772.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0960
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-18398319-AAGTGC-A is Pathogenic according to our data. Variant chr21-18398319-AAGTGC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523101.Status of the report is criteria_provided_single_submitter, 1 stars.

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.151_155delGCACT	p.Ala51TrpfsTer5	frameshift	Exon 2 of 25	NP_002763.3	P98073
	TMPRSS15	NM_001428056.1		c.151_155delGCACT	p.Ala51TrpfsTer5	frameshift	Exon 4 of 29	NP_001414985.1
	TMPRSS15	NM_001428057.1		c.151_155delGCACT	p.Ala51TrpfsTer5	frameshift	Exon 4 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.151_155delGCACT	p.Ala51TrpfsTer5	frameshift	Exon 2 of 25	ENSP00000284885.3	P98073
	TMPRSS15	ENST00000422787.1	TSL:5	c.16_20delGCACT	p.Ala6TrpfsTer5	frameshift	Exon 2 of 8	ENSP00000398253.1	E9PG70
	TMPRSS15	ENST00000474775.1	TSL:5	c.-277-14546_-277-14542delGCACT		intron	N/A	ENSP00000474811.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Enterokinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.096
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555909961; hg19: chr21-19770636;