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7-142750600-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4

The NM_002769.5(PRSS1):c.86A>T(p.Asn29Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,417,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 37)
Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

2
13

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13U:2O:1

Conservation

PhyloP100: 1.38
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_002769.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-142750600-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 38366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 7-142750600-A-T is Pathogenic according to our data. Variant chr7-142750600-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142750600-A-T is described in UniProt as null. Variant chr7-142750600-A-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.008056939).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRSS1NM_002769.5 linkuse as main transcriptc.86A>T p.Asn29Ile missense_variant 2/5 ENST00000311737.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRSS1ENST00000311737.12 linkuse as main transcriptc.86A>T p.Asn29Ile missense_variant 2/51 NM_002769.5 P1
PRSS1ENST00000486171.5 linkuse as main transcriptc.86A>T p.Asn29Ile missense_variant 2/65
PRSS1ENST00000497041.1 linkuse as main transcriptn.90A>T non_coding_transcript_exon_variant 2/22
PRSS1ENST00000485223.1 linkuse as main transcriptn.54-29A>T intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
37
GnomAD4 exome
AF:
0.00000635
AC:
9
AN:
1417370
Hom.:
0
Cov.:
85
AF XY:
0.00000567
AC XY:
4
AN XY:
705934
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000238
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000742
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
37
Alfa
AF:
0.184
Hom.:
0
ExAC
AF:
0.470
AC:
57066

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary pancreatitis Pathogenic:9Uncertain:1Other:1
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant c.86A>T (p.Asn29Ile) in the PRSS1 gene has been reported in multiple individuals affected with hereditary pancreatitis (Chen et al., 2009). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects PRSS1 function (Szabó et al., 2012). The frequency data for this variant in the population databases are considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported to the ClinVar database as Uncertain significance/Pathogenic (Multiple Submissions). The amino acid Asparagine at position 29 is changed to an Isoleucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn29Ile in PRSS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 24, 2023This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 29 of the PRSS1 protein (p.Asn29Ile). 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 individual(s) with hereditary pancreatitis (PMID: 2539344, 18755888, 19453252). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn21Ile. ClinVar contains an entry for this variant (Variation ID: 11877). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 10801865, 11097832, 22539344). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PRSS1 p.Asn29Ile variant was identified in the literature associated with chronic and acute recurrent pancreatitis (Howes_2004_15017610). In a European cohort of 418 individuals with either chronic or acute recurrent pancreatitis, 94 were heterozygous for the p.Asn29Ile variant, 7 of which developed pancreatic cancer (Howes_2004_15017610). The p.Asn29Ile variant was associated with a 4-5 year delayed onset of disease presentation  compared to individuals with the common R122H variant in PRSS1(Howes_2004_15017610). Moreover, women and patients with the p.Asn29Ile variant underwent pancreatic resection for pain much earlier than males and those with wild-type or different PRSS1 mutations, respectively(Howes_2004_15017610). The p.Asn29Ile variant was also identified in 1 of 92 unrelated Mexican children (Sanchez-Ramirez_2012_22699143) and 2 of 92 unrelated Polish children (Sobczyńska-Tomaszewska_2006_16954950) with chronic or acute recurrent pancreatitis, however the number of subjects with chronic or acute recurrent pancreatitis bearing the PRSS1 p.Asn29Ile variant was not significantly different from controls. In a cohort of 71 Korean patients with chronic pancreatitis (alcoholic: 47, idiopathic: 22, and familial: 2), 0 carried the  p.Asn29Ile variant (Lee_2004_15329520).  The PRSS1 p.Asn29Ile variant was identified in dbSNP (rs111033566) and ClinVar (conflicting predictions; 6 pathogenic and 1 benign). In vitro studies suggest that the p.Asn29Ile variant increases autoactivation of human cationic trypsinogen (Tg-1) under acidic conditions, which might be relevant to the pathomechanism of the p.Asn21Ile mutation in hereditary pancreatitis (Sahin-Toth_2000_10801865). The variant was identified in the ExAC control database in 57,066 of 121,412 chromosomes (0 homozygous) at a frequency of 47%, and was observed at the highest frequency in the South Asian (SAS) population in 16,362 alleles (freq:49.1077%). The variant was not identified in the Gnomad database. The p.Asn29Ile residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, It is possible that the p.Asn29Ile variant acts as a risk allele for hereditary pancreatitis. However, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.PRSS1 is associated with autosomal dominant hereditary pancreatitis (Phenotype MIM number: 167800). Pancreatitis is characterized by inflammation of the pancreas. In some individuals it may progress from acute (sudden onset; duration <6 months) to recurrent acute (>1 episode of acute pancreatitis) to chronic (duration >6 months). The range of symptoms and disease course vary from person to person. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016Across a selection of available literature, the c.86A>T (p.Asn29Ile) variant, also referred to as p.Asn21Ile, has been reported in at least 160 hereditary pancreatitis (HP) patients (Gorry et al. 1997; Ferec et al. 1997; Otsuki et al. 2004; Sahin-Toth et al. 2006; Lee et al. 2011; Wang et al. 2013). Gorry et al. (1997) first reported the p.Asn29Ile variant in two unrelated pedigrees. Both had an extensive history of HP with one pedigree with 15 affected family members who all shared the p.Asn29Ile variant. In addition, in a review of a variant database maintained by Leipzig University in Germany, Sahin-Toth et al. (2006) observed that the p.Asn29Ile variant was the second most common PRSS1 variant associated with HP, accounting for approximately 25% of all identified pathogenic alleles in PRSS1. The p.Asn29Ile variant was absent from 382 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. To evaluate the functional impact of the p.Asn29Ile variant, wild-type and variant trypsinogen were expressed in either E. coli or HEK293T cells. Presence of the p.Asn29Ile variant resulted in an increased rate of trypsinogen autoactivation compared to wild type, thereby also increasing trypsin levels (Szabo et al. 2012). Based on the collective evidence, the p.Asn29Ile variant is classified as pathogenic for hereditary pancreatitis. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 29, 2021The p.N29I pathogenic mutation (also known as c.86A>T), located in coding exon 2 of the PRSS1 gene, results from an A to T substitution at nucleotide position 86. The asparagine at codon 29 is replaced by isoleucine, an amino acid with dissimilar properties. This mutation (referred to as p.N21I) was first described in a hereditary pancreatitis (HP) family (Gorry MC et al. Gastroenterology, 1997 Oct;113:1063-8) and was subsequently observed to segregate with disease in 2 additional unrelated HP families (F&eacute;rec C et al. J. Med. Genet., 1999 Mar;36:228-32). In another study, this mutation accounted for 12% of all PRSS1 mutations in a cohort of French individuals with HP (Rebours V et al. Gut, 2009 Jan;58:97-103). In one functional study, this mutation was observed to result in an increase in auto-activation of cationic trypsinogen (Sahin-T&oacute;th M et al. Biochem. Biophys. Res. Commun., 2000 Nov;278:286-9). The p.N29I mutation accounts for approximately 25% of HP families; it increases trypsinogen activation and reduces CTRC-dependent degradation (N&eacute;meth BC et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2014 Mar;306:G466-73). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2000- -
Pathogenic, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsOct 22, 2019- -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Oct 26, 2020- -
not provided, no classification providedliterature onlyGeneReviews-- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 12, 2022The PRSS1 c.86A>T; p.Asn29Ile variant (rs111033566), also known as Asn21Ile, has been reported as a common PRSS1 pathogenic variant in hereditary pancreatitis (Rebours 2009, Rosendahl 2013), and co-segregates with affected individuals in multiple unrelated families (Ferec 1999, Gorry 1997, Teich 1998). Functional analyses reveal that the variant protein has enhanced auto-activation activity in acidic environments, which is predicted to be the pathogenic mechanism (Sahin-Toth 2000a, Sahin-Toth 2000b). This variant is also reported in ClinVar (Variation ID: 11877). The asparagine at codon 29 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.269). Based on available information, this variant is considered to be pathogenic. References: Ferec C et al. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J Med Genet. 1999 Mar;36(3):228-32. PMID: 10204851. Gorry MC et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology. 1997 Oct;113(4):1063-8. PMID: 9322498. Rebours V et al. The natural history of hereditary pancreatitis: a national series. Gut. 2009 Jan;58(1):97-103. PMID: 18755888. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. PMID: 22427236. Sahin-Toth M et al. Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun. 2000a Nov 19;278(2):286-9. PMID: 11097832. Sahin-Toth M. Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis. J Biol Chem. 2000b Jul 28;275(30):22750-5. PMID: 10801865. Teich N et al. Mutations of the cationic trypsinogen in hereditary pancreatitis. Hum Mutat. 1998;12(1):39-43. PMID: 9633818. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023PRSS1: PS4, PM2, PP1:Moderate, PS3:Moderate, PP4 -
Hereditary pancreatitis;C0268417:Trypsinogen deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Vitamin D-dependent rickets type II with alopecia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.N29I in PRSS1 (NM_002769.4) has been previously reported in multiple individuals with hereditary pancreatitis and is the second most common alllele reported with hereditary pancreatitis (Németh et al, 2014; Chen et al, 2009). Though reported in the gnomAD database with a frequency of 28.37%, this estimate is not considered to be true because of poor site quality metrics. Experimental studies have shown that this missense change leads to auto-activation of cationic trypsinogen and results in high levels of activated trypsin in the pancreas (Sahin-Tóth et al, 2000). It has been submitted to the ClinVar database as Pathogenic. There is a large physicochemical difference between asparagine and isoleucine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico predictions do not suggest a damaging effect and the residue is poorly conserved across species. For these reasons, this variant has been classified as Pathogenic -
Myoepithelial tumor Uncertain:1
Uncertain significance, no assertion criteria providedresearchCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell MedicineNov 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Benign
-0.29
Cadd
Benign
21
Dann
Benign
0.91
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.72
D
MetaRNN
Benign
0.0081
T;T;T
MetaSVM
Uncertain
-0.24
T
MutationTaster
Benign
0.00018
A;A
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.9
N;.;N
REVEL
Benign
0.27
Sift
Benign
0.045
D;.;D
Sift4G
Uncertain
0.032
D;D;D
Polyphen
0.0
.;.;B
Vest4
0.098
MPC
0.21
ClinPred
0.013
T
GERP RS
2.6
Varity_R
0.72
gMVP
0.61

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.

Other links and lift over

dbSNP: rs111033566; hg19: chr7-142458451; COSMIC: COSV61191509; COSMIC: COSV61191509; API