Genetic Variant PRSS1:p.Gly151Gly (chr7-142752026-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6BP7BS2_Supporting

The NM_002769.5(PRSS1):c.453C>T(p.Gly151Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,541,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G151G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 splice_region, synonymous

Scores

Splicing: ADA: 0.00005508

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -2.21

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 7-142752026-C-T is Benign according to our data. Variant chr7-142752026-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411135.

BP7

Synonymous conserved (PhyloP=-2.21 with no splicing effect.

BS2

High AC in GnomAd4 at 19 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.453C>T	p.Gly151Gly	splice_region synonymous	Exon 3 of 5	NP_002760.1
PRSS1	NR_172947.1		n.395C>T		splice_region non_coding_transcript_exon	Exon 3 of 5
PRSS1	NR_172948.1		n.392C>T		splice_region non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.453C>T	p.Gly151Gly	splice_region synonymous	Exon 3 of 5	ENSP00000308720.7
PRSS1	ENST00000486171.5	TSL:5	c.495C>T	p.Gly165Gly	splice_region synonymous	Exon 4 of 6	ENSP00000417854.1
PRSS1	ENST00000492062.2	TSL:2	c.453C>T	p.Gly151Gly	splice_region synonymous	Exon 3 of 5	ENSP00000419912.2

Frequencies

GnomAD3 genomes

AF:

0.000147

AC:

AN:

129014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000207

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000202

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000184

AC:

AN:

250360

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.0000947

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000120

AC:

169

AN:

1412206

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

703950

show subpopulations

African (AFR)

AF:

0.0000628

AC:

AN:

31822

American (AMR)

AF:

0.00

AC:

AN:

43324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25374

East Asian (EAS)

AF:

0.000455

AC:

AN:

39590

South Asian (SAS)

AF:

0.000106

AC:

AN:

85010

European-Finnish (FIN)

AF:

0.0000589

AC:

AN:

50942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.000120

AC:

129

AN:

1071858

Other (OTH)

AF:

0.000136

AC:

AN:

58802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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

AF:

0.000147

AC:

AN:

129086

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

62972

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

12806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3018

East Asian (EAS)

AF:

0.000207

AC:

AN:

4824

South Asian (SAS)

AF:

0.00

AC:

AN:

4318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000202

AC:

AN:

59284

Other (OTH)

AF:

0.00

AC:

AN:

1764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00116

Hom.:

Bravo

AF:

0.000159

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:1Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 151 of the PRSS1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PRSS1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 411135). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 30, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not specified

Benign:1

Nov 11, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.11

(source)

DANN

Benign

0.36

PhyloP100

-2.2

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.10

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over