chr7-142750587-G-T

Variant names:

• chr7-142750587-G-T
• rs768051473
• NM_002769.5:c.73G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25A) has been classified 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TRB (HGNC:12155):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 31 uncertain in NM_002769.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002769.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	NM_002769.5	MANE Select	c.73G>T	p.Val25Phe	missense	Exon 2 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.86G>T		non_coding_transcript_exon	Exon 2 of 5
	PRSS1	NR_172948.1		n.86G>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.73G>T	p.Val25Phe	missense	Exon 2 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.73G>T	p.Val25Phe	missense	Exon 2 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.73G>T	p.Val25Phe	missense	Exon 2 of 5	ENSP00000419912.2	H0Y8D1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 38

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.66	P
Vest4		0.73
MutPred		0.66		Loss of ubiquitination at K23 (P = 0.0896)
MVP		0.94
MPC		0.56
ClinPred		0.99	D
GERP RS		1.6
PromoterAI		-0.0075	Neutral
Varity_R		0.81
gMVP		0.88
Mutation Taster		=46/54	disease causing

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

Other links and lift over

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