Genetic Variant NM_002769.5:c.65A>G (chr7-142750579-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_002769.5(PRSS1):c.65A>G(p.Asp22Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D22N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 39)

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.00

Publications

41 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: Orphanet, ClinGen, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

PRSS1 links:

TRB (HGNC:12155):

TRB links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 31 uncertain in NM_002769.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

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
PRSS1	NM_002769.5	MANE Select	c.65A>G	p.Asp22Gly	missense	Exon 2 of 5	NP_002760.1
PRSS1	NR_172947.1		n.78A>G		non_coding_transcript_exon	Exon 2 of 5
PRSS1	NR_172948.1		n.78A>G		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.65A>G	p.Asp22Gly	missense	Exon 2 of 5	ENSP00000308720.7
PRSS1	ENST00000486171.5	TSL:5	c.65A>G	p.Asp22Gly	missense	Exon 2 of 6	ENSP00000417854.1
PRSS1	ENST00000492062.2	TSL:2	c.65A>G	p.Asp22Gly	missense	Exon 2 of 5	ENSP00000419912.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.15

PhyloP100

5.0

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.80

Sift

Benign

0.12

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.78

MutPred

0.84

Loss of ubiquitination at K23 (P = 0.0531)

MVP

0.92

MPC

0.26

ClinPred

0.98

GERP RS

3.5

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.64

gMVP

0.79

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over