rs111033567

chr7-142750582-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_002769.5(PRSS1):c.68A>G(p.Lys23Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K23E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 40)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a propeptide Activation peptide (size 7) in uniprot entity TRY1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-142750582-A-G is Pathogenic according to our data. Variant chr7-142750582-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142750582-A-G is described in UniProt as null. Variant chr7-142750582-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.68A>G	p.Lys23Arg	missense_variant	2/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.68A>G	p.Lys23Arg	missense_variant	2/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.68A>G	p.Lys23Arg	missense_variant	2/6	5
PRSS1	ENST00000497041.1	n.72A>G		non_coding_transcript_exon_variant	2/2	2
PRSS1	ENST00000485223.1	n.54-47A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 40

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 100 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 40

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Apr 19, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PRSS1 protein function (PMID: 10930381, 16036133, 23601753). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 11878). This missense change has been observed in individual(s) with hereditary pancreatitis and pancreatitis (PMID: 10204851, 25383785). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 23 of the PRSS1 protein (p.Lys23Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;.;N
REVEL	Pathogenic	0.67
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.55	.;.;P
Vest4		0.30
MutPred		0.83		Loss of ubiquitination at K23 (P = 0.0141);Loss of ubiquitination at K23 (P = 0.0141);Loss of ubiquitination at K23 (P = 0.0141);
MVP		0.92
MPC		0.15
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.30
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111033567; hg19: chr7-142458433; COSMIC: COSV100297661; COSMIC: COSV100297661;