NM_002769.5:c.86A>T

Variant names:

• chr7-142750600-A-T
• rs111033566
• NM_002769.5:c.86A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3 PM5 PP5 BP4

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000467092: 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)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:3 O:1
• Conservation: PhyloP100: 1.38
• Publications: 188 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000467092: 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).; SCV000552149: Experimental studies have shown that this missense change affects PRSS1 function (PMID: 10801865, 11097832, 22539344).; SCV000604933: 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). PMID: 11097832. PMID: 10801865.; SCV001179405: "In one functional study, this mutation was observed to result in an increase in auto-activation of cationic trypsinogen (Sahin-Tóth M et al. Biochem. Biophys. Res. Commun., 2000 Nov;278:286-9)."; SCV004101512: Experimental studies have shown that this missense change affects PRSS1 function Szabó and Sahin-Tóth, 2012.; SCV001712064: 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).; SCV006279207: "Published functional studies demonstrate a damaging effect: enhances autoactivation of the PRSS1 enzyme as compared to wild-type." PMID:11097832, PMID:22539344, PMID:32547704; SCV005354685: Functional studies indicate the p.Asn29Ile change leads to increased trypsinogen activation (Szabó and Sahin-Tóth. 2012. PubMed ID: 22539344).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-142750600-A-C is described in ClinVar as Pathogenic. ClinVar VariationId 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11877.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008056939). . 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.86A>T	p.Asn29Ile	missense	Exon 2 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.99A>T		non_coding_transcript_exon	Exon 2 of 5
	PRSS1	NR_172948.1		n.99A>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.86A>T	p.Asn29Ile	missense	Exon 2 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.86A>T	p.Asn29Ile	missense	Exon 2 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.86A>T	p.Asn29Ile	missense	Exon 2 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD2 exomes AF: 0.283 AC: 44150 AN: 155926 AF XY: 0.304

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.00000635 AC: 9 AN: 1417370 Hom.: 0 Cov.: 85 AF XY: 0.00000567 AC XY: 4 AN XY: 705934

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

African (AFR) AF: 0.00 AC: 0 AN: 31132

American (AMR) AF: 0.0000238 AC: 1 AN: 41986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 85060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078254

Other (OTH) AF: 0.00 AC: 0 AN: 58568

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000649326), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 37

Alfa AF: 0.184 Hom.: 0

ExAC AF: 0.470 AC: 57066

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
10	2	-	Hereditary pancreatitis (13)
3	-	-	not provided (3)
1	-	-	Hereditary pancreatitis;C0268417:Trypsinogen deficiency (1)
-	1	-	Myoepithelial tumor (1)
1	-	-	PRSS1-related disorder (1)
1	-	-	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.72	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.46	N
PhyloP100		1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.045	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0	B
Vest4		0.098
MPC		0.21
ClinPred		0.013	T
GERP RS		2.6
PromoterAI		-0.012	Neutral
Varity_R		0.72
gMVP		0.61
Mutation Taster		=4/96	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: rs111033566; hg19: chr7-142458451; COSMIC: COSV61191509; COSMIC: COSV61191509;