rs111033564

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_002769.5(PRSS1):c.235G>A(p.Glu79Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 0.360

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:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002769.5

BP4

Computational evidence support a benign effect (BayesDel_addAF=-0.40737).

BS2

High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 3 of 5	ENST00000311737.12	NP_002760.1	P07477

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12 link	c.235G>A	p.Glu79Lys	missense_variant	Exon 3 of 5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251484

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000112

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000177

Hom.:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:1Uncertain:3

Oct 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E79K variant (also known as c.235G>A), located in coding exon 3 of the PRSS1 gene, results from a G to A substitution at nucleotide position 235. The glutamic acid at codon 79 is replaced by lysine, an amino acid with similar properties. This variant has been reported in individuals with chronic and recurrent acute pancreatitis, some of whom have variants in other genes that may contribute to their disease; in addition, the variant has been identified in unaffected family members and healthy controls (Teich N et al. Hum. Mutat., 2004 Jan;23:22-31; Chen JM et al. Clin. Genet., 2001 Mar;59:189-93; Oracz G et al. Pancreatology Apr;16:535-41; Bernardino AL et al. JOP, 2003 Sep;4:169-77; Keiles S et al. Pancreas, 2006 Oct;33:221-7; Hamoir C et al. Digestion, 2013 Jun;87:229-39; Masson E et al. PLoS One, 2013 Aug;8:e73522; Wejnarska K et al. J Pediatr Gastroenterol Nutr, 2016 12;63:665-670). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRSS1 c.235G>A, p.Glu79Lys variant (rs111033564) is reported in the literature in multiple individuals affected with chronic pancreatitis (Bernardino 2003, Chen 2001, Keiles 2006, Rebours 2009, Masson 2013, Teich 2004, Wejnarska 2016), though it has also been reported at similar frequencies in unaffected controls (Bernardino 2003, Chen 2001). Functional characterization of the variant protein indicates no impact on secretion, enzymatic activity, auto-activation or sensitivity to SPINK1 inhibition (Kereszturi 2009, Teich 2004). However, trans-activation of the anionic trypsinogen (PRSS2) was increased two-fold in the presence of p.Glu79Lys variant protein (Teich 2004). This variant is found in the general population with an overall allele frequency of 0.004% (9/251484 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.547). Due to the conflicting information regarding this variant, its clinical significance could not be determined with certainty. References: Bernardino A et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003; 4(5):169-77. PMID: 14526128. Chen J et al. Mutational screening of the cationic trypsinogen gene in a large cohort of subjects with idiopathic chronic pancreatitis. Clin Genet. 2001; 59(3):189-93. PMID: 11260229. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006; 33(3):221-7. PMID: 17003641. Kereszturi E et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009; 30(4):575-82. PMID: 19191323. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. PMID: 23951356. Rebours V et al. The natural history of hereditary pancreatitis: a national series. Gut. 2009; 58(1):97-103. PMID: 18755888. Teich N et al. Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). Hum Mutat. 2004; 23(1):22-31. PMID: 14695529. Wejnarska K et al. The Etiology and Clinical Course of Chronic Pancreatitis in Children With Early Onset of the Disease. J Pediatr Gastroenterol Nutr. 2016 Dec;63(6):665-670. PMID: 27673710. -

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 79 of the PRSS1 protein (p.Glu79Lys). 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 missense change has been observed in individuals with hereditary pancreatitis, idiopathic chronic pancreatitis, and alcohol-related chronic pancreatitis (PMID: 11260229, 14526128, 14695529, 18184119, 23751316, 23951356, 24458023, 27179762). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11880). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRSS1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRSS1 function (PMID: 14695529, 19191323). 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. -

not specified

Uncertain:1

Jan 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRSS1 c.235G>A (p.Glu79Lys) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1615650 control chromosomes, predominantly at a frequency of 0.00024 within the African or African-American subpopulation in the gnomAD v4 database. This frequency is close to the estimated maximal expected allele frequency of a pathogenic PRSS1 causing Chronic Pancreatitis (0.00024 vs 0.00025), suggesting this may be a benign polymorphism. Co-occurrence with a pathogenic variant has been reported following internal testing (SPINK1 c.101A>G, p.Asn34Ser) while, there are at least four reported chronic pancreatitis patients in literature that carry CFTR pathogenic variants (5T allele or p.F508del) along with this variant (Keiles_2006, Masson_2013, Oracz_2016, Sultan_2012). c.235G>A has been reported in the literature in multiple individuals/families affected with chronic pancreatitis, idiopathic chronic pancreatitis, hereditary pancreatitis and alcohol-related chronic pancreatitis as well as in unaffected controls and unaffected family members (e.g. Chen_2001, Bernardino_2003, Teich_2004, Derikx_2009, Rousseau_2012, Hamoir_2013, Oracz_2016, Masson_2023). Functional studies (Teich_2004, Kereszturi_2009) of E79K trypsin revealed unaltered secretion, catalytic activity, autolysis, and inhibition by pancreatic secretory trypsin inhibitor; however, the variant was found to cause increased trypsinogen activation following transactivation of PRSS2. The following publications have been ascertained in the context of this evaluation (PMID: 14526128, 25543846, 11260229, 19857283, 23751316, 17003641, 19191323, 36517351, 23951356, 27179762, 18755888, 22094894, 20452997, 14695529). ClinVar contains an entry for this variant (Variation ID: 11880). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

May 14, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed alone and with variants in CFTR in individuals with idiopathic and familial pancreatitis, as well as unaffected controls (Chen 2001, Bernardino 2003, Rebours 2008, Sultan 2012, Hamoir 2013, Masson 2013, Oracz 2016); Published functional studies are inconclusive: catalytic activity and inhibition by pancreatic secretory trypsin inhibitor similar to wild type and differing results regarding the autoactivation of trypsinogen (Teich 2004, Buettner 2014); This variant is associated with the following publications: (PMID: 27673710, 23474566, 16791840, 14695529, 19191323, 11260229, 23951356, 14526128, 20676769, 24458023, 17003641, 18184119, 22094894, 23751316, 27179762, 25543846) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.25

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.084

M_CAP

Benign

0.012

ClinPred

0.0075

GERP RS

-0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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