NM_002769.5:c.40+3_40+6delGAGT

Variant names:

• chr7-142749524-CGTGA-C
• rs897784116
• NM_002769.5:c.40+3_40+6delGAGT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002769.5(PRSS1):​c.40+3_40+6delGAGT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000206 in 145,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.91
• Publications: 0 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: Orphanet, ClinGen, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant pancreatic neoplasm

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

TRB (HGNC:12155):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	NM_002769.5	MANE Select	c.40+3_40+6delGAGT		splice_region intron	N/A	NP_002760.1
	PRSS1	NR_172947.1		n.53+3_53+6delGAGT		splice_region intron	N/A
	PRSS1	NR_172948.1		n.53+3_53+6delGAGT		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.40+1_40+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000308720.7
	PRSS1	ENST00000486171.5	TSL:5	c.40+1_40+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000417854.1
	PRSS1	ENST00000492062.2	TSL:2	c.40+1_40+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000419912.2

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145690 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000684

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000282 AC: 4 AN: 1418462 Hom.: 0 AF XY: 0.00000142 AC XY: 1 AN XY: 706042

⚠️ 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: 32284

American (AMR) AF: 0.00 AC: 0 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 38772

South Asian (SAS) AF: 0.00 AC: 0 AN: 84610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079588

Other (OTH) AF: 0.0000171 AC: 1 AN: 58572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000100134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000206 AC: 3 AN: 145690 Hom.: 0 Cov.: 34 AF XY: 0.0000423 AC XY: 3 AN XY: 70998

African (AFR) AF: 0.0000256 AC: 1 AN: 39028

American (AMR) AF: 0.0000684 AC: 1 AN: 14624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4998

South Asian (SAS) AF: 0.00 AC: 0 AN: 4576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65880

Other (OTH) AF: 0.00 AC: 0 AN: 1990

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs897784116; hg19: chr7-142457375;