Genetic Variant PRSS1:c.200+1G>A (chr7-142750715-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002769.5(PRSS1):c.200+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.025 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 9.54

Publications

4 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 7-142750715-G-A is Benign according to our data. Variant chr7-142750715-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403350.

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	Effect	Exon Rank	Protein	UniProt
PRSS1	NM_002769.5	MANE Select	c.200+1G>A	splice_donor intron	N/A	NP_002760.1	P07477
PRSS1	NR_172947.1		n.197+17G>A	intron	N/A
PRSS1	NR_172948.1		n.197+17G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.200+1G>A	splice_donor intron	N/A	ENSP00000308720.7	P07477
PRSS1	ENST00000486171.5	TSL:5	c.200+1G>A	splice_donor intron	N/A	ENSP00000417854.1	E7EQ64
PRSS1	ENST00000492062.2	TSL:2	c.200+1G>A	splice_donor intron	N/A	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

2297

AN:

92686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.0224

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00274

Gnomad SAS

AF:

0.00672

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.00510

Gnomad NFE

AF:

0.0170

Gnomad OTH

AF:

0.0235

GnomAD2 exomes

AF:

0.000264

AC:

AN:

226894

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.000741

Gnomad AMR exome

AF:

0.000301

Gnomad ASJ exome

AF:

0.000900

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.000205

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00105

AC:

1374

AN:

1304998

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

872

AN XY:

644014

show subpopulations

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

African (AFR)

AF:

0.00194

AC:

AN:

27272

American (AMR)

AF:

0.000528

AC:

AN:

37906

Ashkenazi Jewish (ASJ)

AF:

0.000802

AC:

AN:

21210

East Asian (EAS)

AF:

0.000630

AC:

AN:

34916

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79148

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

39352

Middle Eastern (MID)

AF:

0.00138

AC:

AN:

5082

European-Non Finnish (NFE)

AF:

0.00109

AC:

1101

AN:

1008766

Other (OTH)

AF:

0.00152

AC:

AN:

51346

⚠️ 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: 0.245

Heterozygous variant carriers

246

491

737

982

1228

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:

0.0248

AC:

2297

AN:

92716

Hom.:

Cov.:

AF XY:

0.0261

AC XY:

1188

AN XY:

45562

show subpopulations

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

African (AFR)

AF:

0.0474

AC:

1003

AN:

21148

American (AMR)

AF:

0.0233

AC:

218

AN:

9344

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

2198

East Asian (EAS)

AF:

0.00275

AC:

AN:

4370

South Asian (SAS)

AF:

0.00674

AC:

AN:

3710

European-Finnish (FIN)

AF:

0.0353

AC:

221

AN:

6258

Middle Eastern (MID)

AF:

0.00549

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.0170

AC:

742

AN:

43588

Other (OTH)

AF:

0.0232

AC:

AN:

1294

⚠️ 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: 0.242

Heterozygous variant carriers

375

750

1124

1499

1874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

104

130

<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:

0.0496

Hom.:

ExAC

AF:

0.0177

AC:

2150

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (4)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

PhyloP100

9.5

GERP RS

3.5

PromoterAI

-0.092

Neutral

(source)

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -34

DS_DL_spliceai

0.99

Position offset: -1

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

Computational scores

Splicing

Publications

Other links and lift over