rs397507440

Variant names:

• chr7-142751988-T-A
• rs397507440
• NM_002769.5:c.415T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PS3 PM5 PP3_Strong PP5 BS2_Supporting

The NM_002769.5(PRSS1):​c.415T>A​(p.Cys139Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001519545: At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant resulted in reduced secretion of trypsinogen and induced ER-stress in mammalian cells (e.g. Kereszturi_2009).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C139F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.76
• Publications: 11 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001519545: At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant resulted in reduced secretion of trypsinogen and induced ER-stress in mammalian cells (e.g. Kereszturi_2009).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-142751989-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 618848.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-142751988-T-A is Pathogenic according to our data. Variant chr7-142751988-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38362.
• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.415T>A	p.Cys139Ser	missense	Exon 3 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.357T>A		non_coding_transcript_exon	Exon 3 of 5
	PRSS1	NR_172948.1		n.354T>A		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.415T>A	p.Cys139Ser	missense	Exon 3 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.457T>A	p.Cys153Ser	missense	Exon 4 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.415T>A	p.Cys139Ser	missense	Exon 3 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461884 Hom.: 0 Cov.: 62 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary pancreatitis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.093
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.78
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.052	B
Vest4		0.83
MutPred		0.85		Gain of disorder (P = 0.0016)
MVP		0.91
MPC		0.70
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.75
gMVP		0.90
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397507440; hg19: chr7-142459839;