7-142750630-T-C

Position:

• chr7-142750630-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_002769.5(PRSS1):​c.116T>C​(p.Val39Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 37)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.78

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Alpha-trypsin chain 1 (size 98) in uniprot entity TRY1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 7-142750630-T-C is Pathogenic according to our data. Variant chr7-142750630-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1454580.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-142750630-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.116T>C	p.Val39Ala	missense_variant	2/5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.116T>C	p.Val39Ala	missense_variant	2/5	1	NM_002769.5	ENSP00000308720	P1

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 37

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2021

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects PRSS1 protein function (PMID: 22539344). This variant has been observed in individual(s) with chronic pancreatitis (PMID: 16227369). It has also been observed to segregate with disease in related individuals. This sequence change replaces valine with alanine at codon 39 of the PRSS1 protein (p.Val39Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;.;D
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.1	.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Pathogenic	0.76
Sift	Benign	0.23	T;.;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.83	.;.;P
Vest4		0.54
MutPred		0.94		Gain of disorder (P = 0.0498);Gain of disorder (P = 0.0498);Gain of disorder (P = 0.0498);
MVP		0.86
MPC		0.60
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.49
gMVP		0.86

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: rs397507439; hg19: chr7-142458481;