chr7-142749524-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_002769.5(PRSS1):c.40C>T(p.Leu14Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,418,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L14V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense, splice_region

Scores

Splicing: ADA: 0.0003922

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.00

Publications

8 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15009022).

BS2

High AC in GnomAdExome4 at 66 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.40C>T	p.Leu14Phe	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000311737.12	NP_002760.1	P07477

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12 link	c.40C>T	p.Leu14Phe	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251470

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1418462

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

706042

show subpopulations

African (AFR)

AF:

0.0000310

AC:

AN:

32284

American (AMR)

AF:

0.00

AC:

AN:

43254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.0000516

AC:

AN:

38772

South Asian (SAS)

AF:

0.00

AC:

AN:

84610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.0000556

AC:

AN:

1079588

Other (OTH)

AF:

0.0000512

AC:

AN:

58572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.000128

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2

May 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L14F variant (also known as c.40C>T), located in coding exon 1 of the PRSS1 gene, results from a C to T substitution at nucleotide position 40. The leucine at codon 14 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 14 of the PRSS1 protein (p.Leu14Phe). 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: 528768). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.26

.;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.45

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.1

.;.;L

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.77

N;.;N

REVEL

Benign

0.21

Sift

Benign

0.32

T;.;T

Sift4G

Benign

0.72

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.18

MutPred

0.39

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.85

MPC

0.18

ClinPred

0.026

GERP RS

2.4

Varity_R

0.039

gMVP

0.64

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.056

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over