Genetic Variant NM_002769.5:c.40C>A (chr7-142749524-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002769.5(PRSS1):c.40C>A(p.Leu14Ile) variant causes a missense, splice region 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. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. L14V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PRSS1
NM_002769.5 missense, splice_region

Scores

Splicing: ADA: 0.00009541

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

PRSS1 links:

TRB (HGNC:12155):

TRB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17981836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002769.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRSS1	NM_002769.5	MANE Select	c.40C>A	p.Leu14Ile	missense splice_region	Exon 1 of 5	NP_002760.1	P07477
PRSS1	NR_172947.1		n.53C>A		splice_region non_coding_transcript_exon	Exon 1 of 5
PRSS1	NR_172948.1		n.53C>A		splice_region non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.40C>A	p.Leu14Ile	missense splice_region	Exon 1 of 5	ENSP00000308720.7	P07477
PRSS1	ENST00000486171.5	TSL:5	c.40C>A	p.Leu14Ile	missense splice_region	Exon 1 of 6	ENSP00000417854.1	E7EQ64
PRSS1	ENST00000492062.2	TSL:2	c.40C>A	p.Leu14Ile	missense splice_region	Exon 1 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.0011

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.23

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.085

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

PhyloP100

2.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.87

REVEL

Benign

0.18

Sift

Benign

0.13

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.16

MutPred

0.39

Loss of catalytic residue at L14 (P = 0.1652)

MVP

0.79

MPC

0.18

ClinPred

0.36

GERP RS

2.4

PromoterAI

-0.084

Neutral

(source)

Varity_R

0.039

gMVP

0.57

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000095

dbscSNV1_RF

Benign

0.056

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over