chr7-142750607-G-C

Variant names:

• chr7-142750607-G-C
• rs745623963
• NM_002769.5:c.93G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002769.5(PRSS1):​c.93G>C​(p.Glu31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E31K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.133
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.93G>C	p.Glu31Asp	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.93G>C	p.Glu31Asp	missense_variant	Exon 2 of 5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 Cov.: 84 AF XY: 0.00 AC XY: 0 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111818

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 37

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Feb 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E31D variant (also known as c.93G>C), located in coding exon 2 of the PRSS1 gene, results from a G to C substitution at nucleotide position 93. The glutamic acid at codon 31 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.35	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.043	N
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.53	.;.;N
PhyloP100		-0.13
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.77	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.29	T;.;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.24
MutPred		0.30		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.65
MPC		0.15
ClinPred		0.17	T
GERP RS		-1.5
PromoterAI		0.043	Neutral
Varity_R		0.24
gMVP		0.52
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 22

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

Other links and lift over

dbSNP: rs745623963; hg19: chr7-142458458;