rs77200626

Positions:

chr21-18312975-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PVS1PP5BS1_Supporting

The NM_002772.3(TMPRSS15):c.2135C>G(p.Ser712Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00133 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

TMPRSS15
NM_002772.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 4.42

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 21-18312975-G-C is Pathogenic according to our data. Variant chr21-18312975-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4164.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}. Variant chr21-18312975-G-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0014 (2051/1461716) while in subpopulation NFE AF= 0.00176 (1958/1111876). AF 95% confidence interval is 0.0017. There are 2 homozygotes in gnomad4_exome. There are 983 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS15	NM_002772.3 linkuse as main transcript	c.2135C>G	p.Ser712Ter	stop_gained	18/25	ENST00000284885.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS15	ENST00000284885.8 linkuse as main transcript	c.2135C>G	p.Ser712Ter	stop_gained	18/25	1	NM_002772.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00113

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000628

AC:

158

AN:

251438

Hom.:

AF XY:

0.000618

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00140

AC:

2051

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

983

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00176

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000644

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000672

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Enterokinase deficiency

Pathogenic:5Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 08, 2022	The TMPRSS15 c.2135C>G variant is classified as Pathogenic (PVS1, PM2, PP1) The TMPRSS15 c.2135C>G variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 712. The variant is rare in population databases (gnomAD allele frequency = 0.064%; 98 het and 0 hom in 152120 sequenced alleles; highest frequency = 0.11%, Non-Finnish European population) (PM2). This variant has been reported to segregate with congenital enteropeptidase deficiency in a family with 2 affected siblings (PMID: 11719902) ); PP1). The variant has been reported in dbSNP (rs77200626) and has been reported with Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 4164). It has not been reported in HGMD. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostics Department, Viafet Genomics Laboratory	Aug 23, 2021	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant is present in exon 18/25 in the only transcript of this gene. Several loss-of-function variants are reported as disease-causing in HGMD and/or ClinVar after this position. Holzinger et al., 2002 have identified this variant in a compound heterozygous state in 2 siblings affected with Enterokinase deficiency (PMID: 11719902). -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Ser712*) in the TMPRSS15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS15 are known to be pathogenic (PMID: 11719902). This variant is present in population databases (rs77200626, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with congenital enteropeptidase deficiency (PMID: 11719902). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4164). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20981092, 11719902, 22344438, 29431110, 1147667, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	TMPRSS15: PVS1, PM3, PM2:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

Vest4

0.35

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over