7-142750715-G-A

Position:

chr7-142750715-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_002769.5(PRSS1):c.200+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.025 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 9.54

Variant links:

Genes affected

PRSS1 (HGNC:9475): (serine protease 1) This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is secreted by the pancreas and cleaved to its active form in the small intestine. It is active on peptide linkages involving the carboxyl group of lysine or arginine. Mutations in this gene are associated with hereditary pancreatitis. This gene and several other trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. [provided by RefSeq, Jul 2008]

PRSS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 7-142750715-G-A is Benign according to our data. Variant chr7-142750715-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403350.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5 linkuse as main transcript	c.200+1G>A		splice_donor_variant		ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12 linkuse as main transcript	c.200+1G>A		splice_donor_variant		1	NM_002769.5	ENSP00000308720	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

2297

AN:

92686

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.0224

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00274

Gnomad SAS

AF:

0.00672

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.00510

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0235

GnomAD3 exomes

AF:

0.000264

AC:

AN:

226894

Hom.:

AF XY:

0.000276

AC XY:

AN XY:

123216

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.000301

Gnomad ASJ exome

AF:

0.000900

Gnomad EAS exome

AF:

0.0000553

Gnomad SAS exome

AF:

0.000212

Gnomad FIN exome

AF:

0.000205

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00105

AC:

1374

AN:

1304998

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

872

AN XY:

644014

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.000528

Gnomad4 ASJ exome

AF:

0.000802

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.00109

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0248

AC:

2297

AN:

92716

Hom.:

Cov.:

AF XY:

0.0261

AC XY:

1188

AN XY:

45562

show subpopulations

Gnomad4 AFR

AF:

0.0474

Gnomad4 AMR

AF:

0.0233

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00275

Gnomad4 SAS

AF:

0.00674

Gnomad4 FIN

AF:

0.0353

Gnomad4 NFE

AF:

0.0170

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0496

Hom.:

ExAC

AF:

0.0177

AC:

2150

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	The PRSS1 c.200+1G>A variant (rs143909348) has been reported in an individual with chronic alcohol intake, but no presentation of pancreatitis (Chen 2003). This variant is also reported in ClinVar (Variation ID: 403350), and is found in the general population with an overall allele frequency of 0.46% (1128/246316 alleles, including a single homozygote) in the Genome Aggregation Database, but is considered a low confidence variant in the database. This variant disrupts the canonical splice donor site of intron 2, which is likely to negatively impact gene function. However, the loss of PRSS1 activity has been suggested to be protective against pancreatitis, and is supported by the absence of any nonsense or canonical splice site variants associated with hereditary pancreatitis (Chen 2003). Furthermore, loss-of-function variants in SPINK1, which is a PRSS1 inhibitor, are causative of hereditary pancreatitis (Chen 2000). Although the PRSS1 c.200+1G>A variant is considered unlikely to be disease-causing for pancreatitis, it is unknown if the variant could be associated with other clinical symptoms. References: Chen J et al. Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. J Med Genet. 2000; 37(1):67-9. Chen J et al. "Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. Mol Genet Metab. 2003; 79(1):67-70. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 25, 2023	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 403350). This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 2 of the PRSS1 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), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PRSS1 cause disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2022	Variant summary: PRSS1 c.200+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. As the molecular disease mechanism for PRSS1 mediated Chronic Pancreatitis is gain of function, loss of function variants in PRSS1 are not consistent with the established mechanism. The variant allele was found at a frequency of 0.00026 in 226894 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.058 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRSS1 causing Chronic Pancreatitis Risk phenotype (0.00025), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.200+1G>A in individuals affected with Chronic Pancreatitis (CP) Risk and no experimental evidence demonstrating its impact on protein function have been reported. This variant is listed with a clinical significance of protective in one record of non-CP carriers reported in the "Genetic Risk Factors in Chronic Pancreatitis" database. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Does not pass quality filter; published as protective factor against pancreatitis -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

MutationTaster

Benign

1.0

D;D

GERP RS

3.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -34

DS_DL_spliceai

0.99

Position offset: -1

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