7-142749524-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BS1BS2_Supporting

The NM_002769.5(PRSS1):c.40C>G(p.Leu14Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,200,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.35 ( 0 hom., cov: 32)

Exomes 𝑓: 0.016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRSS1
NM_002769.5 missense, splice_region

Scores

Splicing: ADA: 0.00001884

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.00

Variant links:

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 links:

TRB (HGNC:12155):

TRB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09526378).

BP6

Variant 7-142749524-C-G is Benign according to our data. Variant chr7-142749524-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 939930.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}. Variant chr7-142749524-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0163 (19530/1200316) while in subpopulation AFR AF= 0.0302 (753/24938). AF 95% confidence interval is 0.0284. There are 0 homozygotes in gnomad4_exome. There are 9903 alleles in male gnomad4_exome subpopulation. Median coverage is 48. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 19530 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS1	NM_002769.5 link	c.40C>G	p.Leu14Val	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000311737.12	NP_002760.1	P07477

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRSS1	ENST00000311737.12 link	c.40C>G	p.Leu14Val	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_002769.5	ENSP00000308720.7	P07477
PRSS1	ENST00000486171.5 link	c.40C>G	p.Leu14Val	missense_variant, splice_region_variant	Exon 1 of 6	5		ENSP00000417854.1	E7EQ64
PRSS1	ENST00000485223.1 link	n.53C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2
PRSS1	ENST00000497041.1 link	n.44C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

37367

AN:

106968

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.413

Gnomad AMI

AF:

0.335

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.351

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.348

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251470

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0163

AC:

19530

AN:

1200316

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

9903

AN XY:

595766

show subpopulations

Gnomad4 AFR exome

AF:

0.0302

Gnomad4 AMR exome

AF:

0.0266

Gnomad4 ASJ exome

AF:

0.0367

Gnomad4 EAS exome

AF:

0.0149

Gnomad4 SAS exome

AF:

0.00236

Gnomad4 FIN exome

AF:

0.0869

Gnomad4 NFE exome

AF:

0.0136

Gnomad4 OTH exome

AF:

0.0244

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff

AF:

0.349

AC:

37402

AN:

107048

Hom.:

Cov.:

AF XY:

0.344

AC XY:

18068

AN XY:

52466

show subpopulations

Gnomad4 AFR

AF:

0.413

Gnomad4 AMR

AF:

0.356

Gnomad4 ASJ

AF:

0.351

Gnomad4 EAS

AF:

0.106

Gnomad4 SAS

AF:

0.169

Gnomad4 FIN

AF:

0.353

Gnomad4 NFE

AF:

0.344

Gnomad4 OTH

AF:

0.343

Alfa

AF:

0.115

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2Benign:2

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 14 of the PRSS1 protein (p.Leu14Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 939930). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 11, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 21, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.40C>G (p.Leu14Val) in the PRSS1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. The amino acid Leu at position 14 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-probably damaging, SIFT-damaging and Mutation Taster-disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Leu14Val in PRSS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.7

DANN

Benign

0.10

DEOGEN2

Benign

0.19

.;.;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.020

M_CAP

Benign

0.082

MetaRNN

Benign

0.095

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

-0.055

.;.;N

PrimateAI

Benign

0.35

PROVEAN

Benign

1.4

N;.;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.10

MVP

0.75

MPC

0.16

ClinPred

0.063

GERP RS

2.4

Varity_R

0.035

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.17

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over