rs144422014

Variant names:

• chr7-142750675-A-G
• rs144422014
• NM_002769.5:c.161A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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. 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. 14/21 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. N54T) has been classified as Uncertain significance.

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: -1.85
• Publications: 24 publications found

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

TRB (HGNC:12155):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0784502).
• BP6: Variant 7-142750675-A-G is Benign according to our data. Variant chr7-142750675-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11881.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.161A>G	p.Asn54Ser	missense_variant	Exon 2 of 5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.161A>G	p.Asn54Ser	missense_variant	Exon 2 of 5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes AF: 0.279 AC: 23289 AN: 83508 Hom.: 0 Cov.: 32

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: 55 AN: 208936 AF XY: 0.000247

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.: 0 Cov.: 61 AF XY: 0.0541 AC XY: 26862 AN XY: 496076

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

African (AFR) AF: 0.112 AC: 2129 AN: 19062

American (AMR) AF: 0.164 AC: 3595 AN: 21874

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 1812 AN: 13516

East Asian (EAS) AF: 0.0273 AC: 745 AN: 27274

South Asian (SAS) AF: 0.0350 AC: 1916 AN: 54672

European-Finnish (FIN) AF: 0.206 AC: 4779 AN: 23156

Middle Eastern (MID) AF: 0.0482 AC: 171 AN: 3546

European-Non Finnish (NFE) AF: 0.0386 AC: 31142 AN: 806064

Other (OTH) AF: 0.0676 AC: 2643 AN: 39094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.279 AC: 23329 AN: 83602 Hom.: 0 Cov.: 32 AF XY: 0.273 AC XY: 11220 AN XY: 41066

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

African (AFR) AF: 0.379 AC: 8436 AN: 22236

American (AMR) AF: 0.270 AC: 2207 AN: 8184

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 491 AN: 1822

East Asian (EAS) AF: 0.0620 AC: 238 AN: 3838

South Asian (SAS) AF: 0.0988 AC: 312 AN: 3158

European-Finnish (FIN) AF: 0.285 AC: 1674 AN: 5876

Middle Eastern (MID) AF: 0.195 AC: 32 AN: 164

European-Non Finnish (NFE) AF: 0.259 AC: 9497 AN: 36636

Other (OTH) AF: 0.268 AC: 314 AN: 1172

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.462 Hom.: 7252

ExAC AF: 0.0360 AC: 4370

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1 Uncertain:1 Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

- -

not specified Benign:1

Jul 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRSS1 c.161A>G (p.Asn54Ser) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.049 in 1008258 control chromosomes. The observed variant frequency is approximately 194 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRSS1 causing Chronic Pancreatitis phenotype (0.00025). c.161A>G has been observed in individual(s) affected with Chronic Pancreatitis, however it was part of a PRSS1/PRSS2 hybrid gene created by gene conversion and was in cis with a known pathogenic variant, p.N29I (e.g. Teich_2005). Functional experiments indicated that the N29I mutation was solely responsible for the phenotypic change, resulting in the same level of increased susceptibility for spontaneous activation to trypsin as the double mutant, and found that N54S alone had no effect on the autocatalytic activation of cationic trypsinogen (e.g. Teich_2005). The following publication has been ascertained in the context of this evaluation (PMID: 15776435). ClinVar contains an entry for this variant (Variation ID: 11881). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.079	T
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	N
MetaRNN	Benign	0.078	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.23	.;.;N;.
PhyloP100		-1.8
PrimateAI	Benign	0.26	T
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	T
GERP RS		-6.3
PromoterAI		-0.044	Neutral
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

Other links and lift over

dbSNP: rs144422014; hg19: chr7-142458526; COSMIC: COSV61190712; COSMIC: COSV61190712;