dbSNP rs111033565: PRSS1:p.Arg122His (chr7-142751938-G-A) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1PS3PM1PM5PP5_Very_Strong

The NM_002769.5(PRSS1):c.365G>A(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000053050: Experimental evidence evaluating an impact on protein function demonstrated the variant to increase autolytic stability of trypsin and enhance autocatalytic trypsin generation (Sahin-Toth_2000), resulting in a gain of function effect." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 0.140

Publications

233 publications found

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 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Illumina, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

PRSS1 links:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002769.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS1

Transcript NM_002769.5 (PRSS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000053050: Experimental evidence evaluating an impact on protein function demonstrated the variant to increase autolytic stability of trypsin and enhance autocatalytic trypsin generation (Sahin-Toth_2000), resulting in a gain of function effect.; SCV000552151: Experimental studies have shown that this missense change affects PRSS1 function (PMID: 11097832, 11748242).; SCV000604930: This variant increases the auto-activation and stability of trypsin, even in the presence of inhibitory factors such as chymotrypsin C (Sahin-Toth 2000, Szabo 2012, Whitcomb 1996), and leads to chronic pancreatic inflammation and acinar cell necrosis in a mouse model (Archer 2006). PMID: 17087933. PMID: 24458023. PMID: 11097832. PMID: 22539344. PMID: 8841182.; SCV001182352: An in vitro study demonstrated that this mutation results in a markedly higher active trypsin level compared to wild type and is resistant to degradation (Szabó, 2012).; SCV004013551: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11097832, 11748242, 31419436).; SCV004047387: Experimental studies have shown that this missense change leads to an increase in both PRSS1 stability and trypsinogen activity, due to an inhibition of autolysis (Kukor et. al., 2002; Sahin-Tóth et. al., 2000).; SCV000568661: Functional studies demonstrated that the R122H variant significantly enhanced autoactivation of cationic trypsinogen in vitro and inhibited autocatalytic inactivation of trypsin (Sahin-Toth et al., 2000).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_002769.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-142751937-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 7-142751938-G-A is Pathogenic according to our data. Variant chr7-142751938-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002769.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRSS1	NM_002769.5	MANE Select	c.365G>A	p.Arg122His	missense	Exon 3 of 5	NP_002760.1	P07477
PRSS1	NR_172947.1		n.307G>A		non_coding_transcript_exon	Exon 3 of 5
PRSS1	NR_172948.1		n.304G>A		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.365G>A	p.Arg122His	missense	Exon 3 of 5	ENSP00000308720.7	P07477
PRSS1	ENST00000486171.5	TSL:5	c.407G>A	p.Arg136His	missense	Exon 4 of 6	ENSP00000417854.1	E7EQ64
PRSS1	ENST00000492062.2	TSL:2	c.365G>A	p.Arg122His	missense	Exon 3 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes

AF:

0.0000551

AC:

AN:

145178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000157

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:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251304

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000147

AC:

AN:

1428358

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

711842

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000311

AC:

AN:

32204

American (AMR)

AF:

0.00

AC:

AN:

42932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25556

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

85458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

1084514

Other (OTH)

AF:

0.0000337

AC:

AN:

59302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000147888), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000551

AC:

AN:

145292

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

70924

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000156

AC:

AN:

38344

American (AMR)

AF:

0.00

AC:

AN:

14524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.00

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000302

AC:

AN:

66128

Other (OTH)

AF:

0.00

AC:

AN:

1986

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.238

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000850

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (14)

not provided (9)

PRSS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

1.5

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.022

M_CAP

Benign

0.064

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.10

PhyloP100

0.14

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.16

REVEL

Uncertain

0.51

Sift

Benign

0.39

Sift4G

Benign

0.40

Varity_R

0.21

gMVP

0.57

Mutation Taster

=57/43

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over