rs143909348

chr7-142750715-G-Achr7-142750715-G-Cchr7-142750715-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

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:2 B:4
• Conservation: PhyloP100: 9.54

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.203
• 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: {Uncertain_significance=2, Benign=4}.
• BS2: High AC in GnomAdExome at 60 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2297 AN: 92686 Hom.: 0 Cov.: 30 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: 60 AN: 226894 Hom.: 1 AF XY: 0.000276 AC XY: 34 AN XY: 123216

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.: 1 Cov.: 41 AF XY: 0.00135 AC XY: 872 AN XY: 644014

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.: 0 Cov.: 30 AF XY: 0.0261 AC XY: 1188 AN XY: 45562

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.: 0

ExAC AF: 0.0177 AC: 2150

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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. -
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. -

not specified Benign:2

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 -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
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

Other links and lift over

dbSNP: rs143909348; hg19: chr7-142458566;