rs386134264

chr7-142749451-GTCC-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The 7-142749451-GTCC-G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PRSS1 NM_002769.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -0.129

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 7-142749451-GTCC-G is Benign according to our data. Variant chr7-142749451-GTCC-G is described in ClinVar as [Likely_benign]. Clinvar id is 36703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5			upstream_gene_variant		ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12			upstream_gene_variant		1	NM_002769.5	P1
PRSS1	ENST00000486171.5			upstream_gene_variant		5
PRSS1	ENST00000485223.1			upstream_gene_variant		2
PRSS1	ENST00000497041.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152084 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251444 Hom.: 1 AF XY: 0.000258 AC XY: 35 AN XY: 135896

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000192 AC: 280 AN: 1461072 Hom.: 0 AF XY: 0.000162 AC XY: 118 AN XY: 726942

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.000760

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: 0.0000378

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152202 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74408

Gnomad4 AFR AF: 0.00412

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000719 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2019

Variant summary: PRSS1 c.-30_-28delTCC is located in the untranscribed region upstream of the PRSS1 gene region. The variant allele was found at a frequency of 0.00049 in 282842 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 98- fold the estimated maximal expected allele frequency for a pathogenic variant in PRSS1 causing Chronic Pancreatitis phenotype (5e-06), strongly suggesting that the variant is benign. c.-30_-28delTCC has been reported in the literature in at least one individual affected with Chronic Pancreatitis (Ferec_1999) without strong evidence for causality such as cosegregation with disease. This report does not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis. At least one publication reports in vitro experimental evidence evaluating trancription of PRSS1 and found that the variant had no significant impact on PRSS1 transcription in mammalian cells (Boulling_2016). These results showed no damaging effect of this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2019

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386134264; hg19: chr7-142457302;