rs754618801

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting

The NM_002769.5(PRSS1):c.304A>G(p.Lys102Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.11

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 links:

PRSS1 (HGNC:):

PRSS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002769.5

BP4

Computational evidence support a benign effect (MetaRNN=0.08429825).

BS2

High AC in GnomAdExome4 at 12 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/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5 linkuse as main transcript	c.304A>G	p.Lys102Glu	missense_variant	3/5	ENST00000311737.12	NP_002760.1	P07477

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12 linkuse as main transcript	c.304A>G	p.Lys102Glu	missense_variant	3/5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251220

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 26, 2019	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PRSS1-related disease. This variant is present in population databases (rs754618801, ExAC 0.01%). This sequence change replaces lysine with glutamic acid at codon 102 of the PRSS1 protein (p.Lys102Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2022	The p.K102E variant (also known as c.304A>G), located in coding exon 3 of the PRSS1 gene, results from an A to G substitution at nucleotide position 304. The lysine at codon 102 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species, and glutamic acid is the reference amino acid in other 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.013

DANN

Benign

0.18

DEOGEN2

Benign

0.32

.;.;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.021

M_CAP

Benign

0.053

MetaRNN

Benign

0.084

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.76

.;.;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.47

N;.;N;N

REVEL

Uncertain

0.44

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.23

MutPred

0.36

Loss of methylation at K116 (P = 0.0116);.;.;.;

MVP

0.52

MPC

0.23

ClinPred

0.048

GERP RS

-5.2

Varity_R

0.32

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over