rs111033566

chr7-142750600-A-Cchr7-142750600-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_002769.5(PRSS1):c.86A>C(p.Asn29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29I) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 37)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.38

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 chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_002769.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-142750600-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-142750600-A-C is Pathogenic according to our data. Variant chr7-142750600-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 38366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-142750600-A-C is described in UniProt as null. Variant chr7-142750600-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.86A>C	p.Asn29Thr	missense_variant	2/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.86A>C	p.Asn29Thr	missense_variant	2/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.86A>C	p.Asn29Thr	missense_variant	2/6	5
PRSS1	ENST00000497041.1	n.90A>C		non_coding_transcript_exon_variant	2/2	2
PRSS1	ENST00000485223.1	n.54-29A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 202 AN: 128636 Hom.: 0 Cov.: 37 FAILED QC

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000680

Gnomad EAS AF: 0.00168

Gnomad SAS AF: 0.00235

Gnomad FIN AF: 0.00294

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000101 AC: 14 AN: 1384888 Hom.: 0 Cov.: 85 AF XY: 0.0000116 AC XY: 8 AN XY: 690856

Gnomad4 AFR exome AF: 0.0000724

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000947

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00157 AC: 202 AN: 128724 Hom.: 0 Cov.: 37 AF XY: 0.00176 AC XY: 111 AN XY: 63126

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000680

Gnomad4 EAS AF: 0.00168

Gnomad4 SAS AF: 0.00235

Gnomad4 FIN AF: 0.00294

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00660 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	Variant summary: PRSS1 c.86A>C (p.Asn29Thr) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 155926 control chromosomes (gnomAD). c.86A>C has been reported in the literature in multiple individuals affected with Chronic Pancreatitis and co-segregated with the disease (Pfutzer_2002, Szmola_2010, Dytz_2015, Xiao_2017). Additionally, in one family, 8 out of 10 individuals carrying this variant developed pancreatitis and penetrance of this variant in this family was 80%, which is the same penetrance rate as the most frequently described R122H and N29I mutations (Dytz_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant results in a gain-of-function that leads to an increased rate of autoactivation and increased trypsin stability (Sahin-Toth_2000, Szabo_2012). In addition, another missense at the same codon, N29I, has been classified as pathogenic in our lab, suggesting that it is a clinically significant residue. One ClinVar submitter (evaluation after 2014) cites this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.52
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.14	N
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.9	N;.;N
REVEL	Benign	0.21
Sift	Benign	0.76	T;.;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.70
MutPred		0.87		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.76
MPC		0.17
ClinPred		0.12	T
GERP RS		2.6
Varity_R		0.60
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs111033566; hg19: chr7-142458451;