chr7-142749524-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: 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: 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.

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.40C>G	p.Leu14Val	missense splice_region	Exon 1 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.53C>G		splice_region non_coding_transcript_exon	Exon 1 of 5
	PRSS1	NR_172948.1		n.53C>G		splice_region non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.40C>G	p.Leu14Val	missense splice_region	Exon 1 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.40C>G	p.Leu14Val	missense splice_region	Exon 1 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.40C>G	p.Leu14Val	missense splice_region	Exon 1 of 5	ENSP00000419912.2	H0Y8D1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Hereditary pancreatitis (5)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.055	N
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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;