rs202003805

Variant names:

• chr7-142750561-C-T
• rs202003805
• NM_002769.5:c.47C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_002769.5(PRSS1):​c.47C>T​(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000287691: Experimental studies have shown that this missense change affects PRSS1 function (PMID:16505482, 22539344)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A16A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (0 hom., cov: 36)
  • Exomes 𝑓: 0.20 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2 O:1
• Conservation: PhyloP100: 0.485
• Publications: 103 publications found

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: Illumina, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TRB (HGNC:12155):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000287691: Experimental studies have shown that this missense change affects PRSS1 function (PMID: 16505482, 22539344).; SCV000604925: "In vitro assays have shown p.Ala16Val to increase cationic trypsinogen activity (Nemoda 2006, Szabo 2012)."; SCV001338959: "In presence of chymotrypsin C, A16V increased the rate of autoactivation compared with wild-type cationic trypsinogen by increasing N-terminal processing," PMID:22427236, PMID:24458023; SCV002634471: "In addition, two functional studies demonstrated increased trypsinogen activation in vitro due to a 4- and 5.8-fold increased rate of chymotrypsin C-mediated N-terminal processing relative to wild type, respectively (Nemoda Z et al. J. Biol. Chem., 2006 Apr;281:11879-86; Szabó A et al. J. Biol. Chem., 2012 Jun;287:20701-10)."; SCV004176558: Experimental studies have shown that this missense change affects PRSS1 function (Szabó et al., 2012).; SCV002520160: Published functional studies demonstrate a damaging effect: increased rate of chymotrypsin C (CTRC)-mediated trypsinogen activation (Nemoda 2006).
• PP5: Variant 7-142750561-C-T is Pathogenic according to our data. Variant chr7-142750561-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054525733). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	NM_002769.5	MANE Select	c.47C>T	p.Ala16Val	missense	Exon 2 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.60C>T		non_coding_transcript_exon	Exon 2 of 5
	PRSS1	NR_172948.1		n.60C>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.47C>T	p.Ala16Val	missense	Exon 2 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.47C>T	p.Ala16Val	missense	Exon 2 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.47C>T	p.Ala16Val	missense	Exon 2 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 45782 AN: 118562 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.0000901 AC: 22 AN: 244118 AF XY: 0.0000679

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.202 AC: 162367 AN: 803306 Hom.: 0 Cov.: 90 AF XY: 0.205 AC XY: 82190 AN XY: 401142

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

African (AFR) AF: 0.387 AC: 7556 AN: 19522

American (AMR) AF: 0.329 AC: 8048 AN: 24442

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 4306 AN: 14544

East Asian (EAS) AF: 0.103 AC: 2918 AN: 28194

South Asian (SAS) AF: 0.119 AC: 6401 AN: 53864

European-Finnish (FIN) AF: 0.368 AC: 12297 AN: 33398

Middle Eastern (MID) AF: 0.187 AC: 612 AN: 3280

European-Non Finnish (NFE) AF: 0.190 AC: 112489 AN: 590836

Other (OTH) AF: 0.220 AC: 7740 AN: 35226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.386 AC: 45818 AN: 118638 Hom.: 0 Cov.: 36 AF XY: 0.381 AC XY: 22029 AN XY: 57794

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

African (AFR) AF: 0.458 AC: 15185 AN: 33144

American (AMR) AF: 0.388 AC: 4494 AN: 11568

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 998 AN: 2616

East Asian (EAS) AF: 0.150 AC: 657 AN: 4390

South Asian (SAS) AF: 0.213 AC: 810 AN: 3806

European-Finnish (FIN) AF: 0.388 AC: 3190 AN: 8218

Middle Eastern (MID) AF: 0.327 AC: 81 AN: 248

European-Non Finnish (NFE) AF: 0.373 AC: 19524 AN: 52308

Other (OTH) AF: 0.380 AC: 616 AN: 1620

⚠️ 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.

Alfa AF: 0.115 Hom.: 0

ExAC AF: 0.0173 AC: 2099

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	1	-	Hereditary pancreatitis (10)
2	-	-	not provided (2)
-	1	-	Recurrent pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	2.8
DANN	Benign	0.31
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.48
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.52
Sift	Benign	0.57	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.16
ClinPred		0.026	T
GERP RS		0.99
PromoterAI		-0.0012	Neutral
Varity_R		0.017
gMVP		0.57
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs202003805; hg19: chr7-142458412; COSMIC: COSV61191325; COSMIC: COSV61191325;