rs1554499664

Variant names:

• chr7-142753004-T-C
• rs1554499664
• NM_002769.5:c.728T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002769.5(PRSS1):​c.728T>C​(p.Ile243Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.65

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]

TRB (HGNC:12155):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Peptidase S1 (size 220) in uniprot entity TRY1_HUMAN there are 19 pathogenic changes around while only 8 benign (70%) in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.728T>C	p.Ile243Thr	missense_variant	Exon 5 of 5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.728T>C	p.Ile243Thr	missense_variant	Exon 5 of 5	1	NM_002769.5	ENSP00000308720.7
PRSS1	ENST00000486171.5	c.770T>C	p.Ile257Thr	missense_variant	Exon 6 of 6	5		ENSP00000417854.1
PRSS1	ENST00000492062.1	c.*132T>C		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000419912.2
PRSS1	ENST00000463701.1	n.1192T>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I243T variant (also known as c.728T>C), located in coding exon 5 of the PRSS1 gene, results from a T to C substitution at nucleotide position 728. The isoleucine at codon 243 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

May 29, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRSS1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 243 of the PRSS1 protein (p.Ile243Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.78
DEOGEN2	Uncertain	0.53	.;.;D
Eigen	Benign	0.058
Eigen_PC	Benign	-0.079
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	0.88	.;.;L
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.027	D;.;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.45
MutPred		0.74		Gain of disorder (P = 0.0239);.;.;
MVP		0.90
MPC		0.73
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.26
gMVP		0.80

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: rs1554499664; hg19: chr7-142460855;