7-142750600-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5PP5BP4

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). 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16U:3O:1

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: Uncertain_significance. The variant received 2 ACMG points.

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

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

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.:

GnomAD2 exomes

AF:

0.283

AC:

44150

AN:

155926

AF XY:

0.304

show subpopulations

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:

AN:

1417370

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

705934

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31132

American (AMR)

AF:

0.0000238

AC:

AN:

41986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25346

East Asian (EAS)

AF:

0.00

AC:

AN:

39362

South Asian (SAS)

AF:

0.00

AC:

AN:

85060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00000742

AC:

AN:

1078254

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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

Cov.:

Alfa

AF:

0.184

Hom.:

ExAC

AF:

0.470

AC:

57066

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (13)

not provided (3)

Hereditary pancreatitis;C0268417:Trypsinogen deficiency (1)

Myoepithelial tumor (1)

PRSS1-related disorder (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

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.72

MetaRNN

Benign

0.0081

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.46

PhyloP100

1.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

REVEL

Benign

0.27

Sift

Benign

0.045

Sift4G

Uncertain

0.032

Polyphen

0.0

Vest4

0.098

MPC

0.21

ClinPred

0.013

GERP RS

2.6

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.72

gMVP

0.61

Mutation Taster

=4/96

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over