rs144422014

Positions:

• chr7-142750675-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -8 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=0.0784502).
• 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/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.161A>G	p.Asn54Ser	missense_variant	2/5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.161A>G	p.Asn54Ser	missense_variant	2/5	1	NM_002769.5	ENSP00000308720	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23289 AN: 83508 Hom.: 0 Cov.: 32 FAILED QC

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

GnomAD4 exome AF: 0.0485 AC: 48932 AN: 1008258 Hom.: 0 Cov.: 61 AF XY: 0.0541 AC XY: 26862 AN XY: 496076

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.0273

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0676

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

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.0620

Gnomad4 SAS AF: 0.0988

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.268

Alfa AF: 0.245 Hom.: 841

ExAC AF: 0.0360 AC: 4370

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 19, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2015	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. -

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;.
MutationTaster	Benign	6.4e-7	A;A
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
Varity_R		0.26
gMVP		0.50

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

Other links and lift over

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