rs747228052

Variant names:

• chr7-142749524-C-A
• rs747228052
• NM_002769.5:c.40C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-142749524-C-A
• chr7-142749524-C-G
• chr7-142749524-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 18/23 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 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

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17981836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.40C>A	p.Leu14Ile	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.40C>A	p.Leu14Ile	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_002769.5	ENSP00000308720.7
PRSS1	ENST00000486171.5	c.40C>A	p.Leu14Ile	missense_variant, splice_region_variant	Exon 1 of 6	5		ENSP00000417854.1
PRSS1	ENST00000485223.1	n.53C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2
PRSS1	ENST00000497041.1	n.44C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Nov 12, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L14I variant (also known as c.40C>A), located in coding exon 1 of the PRSS1 gene, results from a C to A substitution at nucleotide position 40. The leucine at codon 14 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.23	.;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	.;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.87	N;.;N
REVEL	Benign	0.18
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.16
MutPred		0.39		Loss of catalytic residue at L14 (P = 0.1652);Loss of catalytic residue at L14 (P = 0.1652);Loss of catalytic residue at L14 (P = 0.1652);
MVP		0.79
MPC		0.18
ClinPred		0.36	T
GERP RS		2.4
Varity_R		0.039
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs747228052; hg19: chr7-142457375;