NM_002769.5:c.86A>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM5PP5_Very_Strong

The NM_002769.5(PRSS1):c.86A>C(p.Asn29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 15/22 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. N29I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 37)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.38

Publications

188 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: Illumina, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
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

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-142750600-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11877.

PP5

Variant 7-142750600-A-C is Pathogenic according to our data. 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.

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.86A>C	p.Asn29Thr	missense	Exon 2 of 5	NP_002760.1	P07477
PRSS1	NR_172947.1		n.99A>C		non_coding_transcript_exon	Exon 2 of 5
PRSS1	NR_172948.1		n.99A>C		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.86A>C	p.Asn29Thr	missense	Exon 2 of 5	ENSP00000308720.7	P07477
PRSS1	ENST00000486171.5	TSL:5	c.86A>C	p.Asn29Thr	missense	Exon 2 of 6	ENSP00000417854.1	E7EQ64
PRSS1	ENST00000492062.2	TSL:2	c.86A>C	p.Asn29Thr	missense	Exon 2 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes

AF:

0.00157

AC:

202

AN:

128636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000680

Gnomad EAS

AF:

0.00168

Gnomad SAS

AF:

0.00235

Gnomad FIN

AF:

0.00294

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000101

AC:

AN:

1384888

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

690856

show subpopulations

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

African (AFR)

AF:

0.0000724

AC:

AN:

27620

American (AMR)

AF:

0.00

AC:

AN:

39648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24640

East Asian (EAS)

AF:

0.00

AC:

AN:

39200

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00000947

AC:

AN:

1055834

Other (OTH)

AF:

0.0000175

AC:

AN:

57186

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.229

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:

0.00157

AC:

202

AN:

128724

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

111

AN XY:

63126

show subpopulations

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

African (AFR)

AF:

0.00183

AC:

AN:

33866

American (AMR)

AF:

0.00229

AC:

AN:

12668

Ashkenazi Jewish (ASJ)

AF:

0.000680

AC:

AN:

2942

East Asian (EAS)

AF:

0.00168

AC:

AN:

4758

South Asian (SAS)

AF:

0.00235

AC:

AN:

4258

European-Finnish (FIN)

AF:

0.00294

AC:

AN:

8830

Middle Eastern (MID)

AF:

0.00455

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

58620

Other (OTH)

AF:

0.00

AC:

AN:

1768

⚠️ 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: 0.235

Heterozygous variant carriers

113

151

189

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:

0.00660

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.31

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.14

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.20

PhyloP100

1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

1.9

REVEL

Benign

0.21

Sift

Benign

0.76

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.70

MutPred

0.87

Gain of sheet (P = 0.1208)

MVP

0.76

MPC

0.17

ClinPred

0.12

GERP RS

2.6

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.60

gMVP

0.52

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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