chr7-142750675-A-G

Variant names:

• chr7-142750675-A-G
• rs144422014
• NM_002769.5:c.161A>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.161A>G​(p.Asn54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,008,258 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. 14/21 in silico tools predict a benign outcome for this variant. 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. N54K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (0 hom., cov: 32)
  • Exomes 𝑓: 0.049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: -1.85
• Publications: 24 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=0.0784502).
• BP6: Variant 7-142750675-A-G is Benign according to our data. Variant chr7-142750675-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11881.

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.161A>G	p.Asn54Ser	missense	Exon 2 of 5	NP_002760.1	P07477
	PRSS1	NR_172947.1		n.174A>G		non_coding_transcript_exon	Exon 2 of 5
	PRSS1	NR_172948.1		n.174A>G		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS1	ENST00000311737.12	TSL:1 MANE Select	c.161A>G	p.Asn54Ser	missense	Exon 2 of 5	ENSP00000308720.7	P07477
	PRSS1	ENST00000486171.5	TSL:5	c.161A>G	p.Asn54Ser	missense	Exon 2 of 6	ENSP00000417854.1	E7EQ64
	PRSS1	ENST00000492062.2	TSL:2	c.161A>G	p.Asn54Ser	missense	Exon 2 of 5	ENSP00000419912.2	H0Y8D1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 23289 AN: 83508 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0617

Gnomad SAS AF: 0.0983

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.198

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.000263 AC: 55 AN: 208936 AF XY: 0.000247

Gnomad AFR exome AF: 0.000870

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.000935

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000568

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0485 AC: 48932 AN: 1008258 Hom.: 0 Cov.: 61 AF XY: 0.0541 AC XY: 26862 AN XY: 496076

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

African (AFR) AF: 0.112 AC: 2129 AN: 19062

American (AMR) AF: 0.164 AC: 3595 AN: 21874

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 1812 AN: 13516

East Asian (EAS) AF: 0.0273 AC: 745 AN: 27274

South Asian (SAS) AF: 0.0350 AC: 1916 AN: 54672

European-Finnish (FIN) AF: 0.206 AC: 4779 AN: 23156

Middle Eastern (MID) AF: 0.0482 AC: 171 AN: 3546

European-Non Finnish (NFE) AF: 0.0386 AC: 31142 AN: 806064

Other (OTH) AF: 0.0676 AC: 2643 AN: 39094

⚠️ 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: InbreedingCoeff AF: 0.279 AC: 23329 AN: 83602 Hom.: 0 Cov.: 32 AF XY: 0.273 AC XY: 11220 AN XY: 41066

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

African (AFR) AF: 0.379 AC: 8436 AN: 22236

American (AMR) AF: 0.270 AC: 2207 AN: 8184

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 491 AN: 1822

East Asian (EAS) AF: 0.0620 AC: 238 AN: 3838

South Asian (SAS) AF: 0.0988 AC: 312 AN: 3158

European-Finnish (FIN) AF: 0.285 AC: 1674 AN: 5876

Middle Eastern (MID) AF: 0.195 AC: 32 AN: 164

European-Non Finnish (NFE) AF: 0.259 AC: 9497 AN: 36636

Other (OTH) AF: 0.268 AC: 314 AN: 1172

⚠️ 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: 0.462 Hom.: 7252

ExAC AF: 0.0360 AC: 4370

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.0010
DANN	Benign	0.27
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.45	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.13
ClinPred		0.074	T
GERP RS		-6.3
PromoterAI		-0.044	Neutral
Varity_R		0.26
gMVP		0.50
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144422014; hg19: chr7-142458526; COSMIC: COSV61190712; COSMIC: COSV61190712;