chr7-142750587-G-T

Position:

• chr7-142750587-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002769.5(PRSS1):​c.73G>T​(p.Val25Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 38)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

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 6 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, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.73G>T	p.Val25Phe	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.73G>T	p.Val25Phe	missense_variant	2/5	1	NM_002769.5	ENSP00000308720.7
PRSS1	ENST00000486171.5	c.73G>T	p.Val25Phe	missense_variant	2/6	5		ENSP00000417854.1
PRSS1	ENST00000497041.1	n.77G>T		non_coding_transcript_exon_variant	2/2	2
PRSS1	ENST00000485223.1	n.54-42G>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 85 AF XY: 0.00 AC XY: 0 AN XY: 727140

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.: 38

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2024

The p.V25F variant (also known as c.73G>T), located in coding exon 2 of the PRSS1 gene, results from a G to T substitution at nucleotide position 73. The valine at codon 25 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.020	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.66	.;.;P
Vest4		0.73
MutPred		0.66		Loss of ubiquitination at K23 (P = 0.0896);Loss of ubiquitination at K23 (P = 0.0896);Loss of ubiquitination at K23 (P = 0.0896);
MVP		0.94
MPC		0.56
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.81
gMVP		0.88

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: rs768051473; hg19: chr7-142458438; COSMIC: COSV100298578; COSMIC: COSV100298578;