rs397507440

Positions:

• chr7-142751988-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PM1 PM5 PP3_Strong PP5 BS2_Supporting

The NM_002769.5(PRSS1):​c.415T>A​(p.Cys139Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C139F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.76

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a disulfide_bond (size 130) in uniprot entity TRY1_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_002769.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-142751988-T-A is Pathogenic according to our data. Variant chr7-142751988-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38362.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.415T>A	p.Cys139Ser	missense_variant	3/5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.415T>A	p.Cys139Ser	missense_variant	3/5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461884 Hom.: 0 Cov.: 62 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2021	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. Experimental studies have shown that this variant affects PRSS1 protein function (PMID: 19191323). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 38362). This variant has been observed in individual(s) with chronic pancreatitis (PMID: 17003641, 20001681, 24909264). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 139 of the PRSS1 protein (p.Cys139Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2021	Variant summary: PRSS1 c.415T>A (p.Cys139Ser) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249602 control chromosomes (gnomAD). c.415T>A has been reported in the literature in multiple individuals affected with Chronic Pancreatitis (e.g. Keiles_2006, Liu_2009, Szmola_2010, Sahin-Toth_2017). These data indicate that the variant may be associated with disease, but most of the cases were idiopathic and in individuals without a detailed family history or co-segregation studies, providing limited evidence for causality. However, a database for genetic risk factors in chronic pancreatitis (http://pancreasgenetics.org/) reports the variant in multiple patients and classifies the variant as pathogenic. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant resulted in reduced secretion of trypsinogen and induced ER-stress in mammalian cells (e.g. Kereszturi_2009). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;.;D;D
Eigen	Benign	0.093
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	.;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.3	D;.;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.030	D;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.052	B;.;B;.
Vest4		0.83
MutPred		0.85		Gain of disorder (P = 0.0016);.;.;.;
MVP		0.91
MPC		0.70
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.75
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397507440; hg19: chr7-142459839;