rs144422014

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1BP4_ModerateBA1

The NM_002769.5(PRSS1):c.161A>G(p.Asn54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,008,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N54N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 0 hom., cov: 32)

Exomes 𝑓: 0.049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.85

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:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 22 pathogenic changes around while only 5 benign (81%) in NM_002769.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0784502).

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.161A>G	p.Asn54Ser	missense_variant	Exon 2 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.161A>G	p.Asn54Ser	missense_variant	Exon 2 of 5	1	NM_002769.5	ENSP00000308720.7		P07477

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

23289

AN:

83508

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.0617

Gnomad SAS

AF:

0.0983

Gnomad FIN

AF:

0.285

Gnomad MID

AF:

0.198

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.000263

AC:

AN:

208936

AF XY:

0.000247

show subpopulations

Gnomad AFR exome

AF:

0.000870

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.000935

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000568

Gnomad NFE exome

AF:

0.000252

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0485

AC:

48932

AN:

1008258

Hom.:

Cov.:

AF XY:

0.0541

AC XY:

26862

AN XY:

496076

show subpopulations

Gnomad4 AFR exome

AF:

0.112

AC:

2129

AN:

19062

Gnomad4 AMR exome

AF:

0.164

AC:

3595

AN:

21874

Gnomad4 ASJ exome

AF:

0.134

AC:

1812

AN:

13516

Gnomad4 EAS exome

AF:

0.0273

AC:

745

AN:

27274

Gnomad4 SAS exome

AF:

0.0350

AC:

1916

AN:

54672

Gnomad4 FIN exome

AF:

0.206

AC:

4779

AN:

23156

Gnomad4 NFE exome

AF:

0.0386

AC:

31142

AN:

806064

Gnomad4 Remaining exome

AF:

0.0676

AC:

2643

AN:

39094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

7170

14340

21509

28679

35849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

156

312

468

624

780

<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: InbreedingCoeff

AF:

0.279

AC:

23329

AN:

83602

Hom.:

Cov.:

AF XY:

0.273

AC XY:

11220

AN XY:

41066

show subpopulations

Gnomad4 AFR

AF:

0.379

AC:

0.379385

AN:

0.379385

Gnomad4 AMR

AF:

0.270

AC:

0.269673

AN:

0.269673

Gnomad4 ASJ

AF:

0.269

AC:

0.269484

AN:

0.269484

Gnomad4 EAS

AF:

0.0620

AC:

0.0620115

AN:

0.0620115

Gnomad4 SAS

AF:

0.0988

AC:

0.0987967

AN:

0.0987967

Gnomad4 FIN

AF:

0.285

AC:

0.284888

AN:

0.284888

Gnomad4 NFE

AF:

0.259

AC:

0.259226

AN:

0.259226

Gnomad4 OTH

AF:

0.268

AC:

0.267918

AN:

0.267918

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

2288

4576

6865

9153

11441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

266

532

798

1064

1330

<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:

0.462

Hom.:

7252

ExAC

AF:

0.0360

AC:

4370

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:1Uncertain:1Benign:3

Mar 14, 2015

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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.0010

DANN

Benign

0.27

DEOGEN2

Uncertain

0.49

.;.;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.015

MetaRNN

Benign

0.078

T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.23

.;.;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;.;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.45

T;.;T;T

Sift4G

Benign

0.62

T;T;T;T

Polyphen

0.0

.;.;B;.

Vest4

0.040

MPC

0.13

ClinPred

0.074

GERP RS

-6.3

Varity_R

0.26

gMVP

0.50

Mutation Taster

=85/15

polymorphism

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

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