7-142749524-C-G

Variant names:

• chr7-142749524-C-G
• rs747228052
• NM_002769.5:c.40C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 19/24 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L14F) has been classified as Uncertain significance.

• 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:4 B:2
• Conservation: PhyloP100: 2.00
• Publications: 8 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: Likely_benign. The variant received -3 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 VariationId is 939930.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.40C>G	p.Leu14Val	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_002769.5	ENSP00000308720.7

Frequencies

GnomAD3 genomes AF: 0.349 AC: 37367 AN: 106968 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251470 AF XY: 0.00000736

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 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.: 0 Cov.: 48 AF XY: 0.0166 AC XY: 9903 AN XY: 595766

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

African (AFR) AF: 0.0302 AC: 753 AN: 24938

American (AMR) AF: 0.0266 AC: 876 AN: 32880

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 685 AN: 18640

East Asian (EAS) AF: 0.0149 AC: 460 AN: 30876

South Asian (SAS) AF: 0.00236 AC: 175 AN: 74016

European-Finnish (FIN) AF: 0.0869 AC: 2647 AN: 30462

Middle Eastern (MID) AF: 0.0146 AC: 63 AN: 4302

European-Non Finnish (NFE) AF: 0.0136 AC: 12725 AN: 937160

Other (OTH) AF: 0.0244 AC: 1146 AN: 47042

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.349 AC: 37402 AN: 107048 Hom.: 0 Cov.: 32 AF XY: 0.344 AC XY: 18068 AN XY: 52466

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

African (AFR) AF: 0.413 AC: 11811 AN: 28596

American (AMR) AF: 0.356 AC: 3849 AN: 10810

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 868 AN: 2472

East Asian (EAS) AF: 0.106 AC: 433 AN: 4072

South Asian (SAS) AF: 0.169 AC: 597 AN: 3532

European-Finnish (FIN) AF: 0.353 AC: 2616 AN: 7420

Middle Eastern (MID) AF: 0.255 AC: 47 AN: 184

European-Non Finnish (NFE) AF: 0.344 AC: 16453 AN: 47826

Other (OTH) AF: 0.343 AC: 508 AN: 1480

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.115 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Uncertain:3 Benign: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. -

Apr 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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	T
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	N
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.055	.;.;N
PhyloP100		2.0
PrimateAI	Benign	0.35	T
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	T
GERP RS		2.4
PromoterAI		0.14	Neutral
Varity_R		0.035
gMVP		0.63
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs747228052; hg19: chr7-142457375; COSMIC: COSV108141165; COSMIC: COSV108141165;