7-142749516-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The NM_002769.5(PRSS1):c.32C>G(p.Ala11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,234,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (0 hom., cov: 31)
  • Exomes 𝑓: 0.014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.74

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1693314).
• BP6: Variant 7-142749516-C-G is Benign according to our data. Variant chr7-142749516-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1729944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0145 (17874/1234152) while in subpopulation AFR AF= 0.0272 (701/25790). AF 95% confidence interval is 0.0255. There are 0 homozygotes in gnomad4_exome. There are 9109 alleles in male gnomad4_exome subpopulation. Median coverage is 47. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.32C>G	p.Ala11Gly	missense_variant	1/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.32C>G	p.Ala11Gly	missense_variant	1/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.32C>G	p.Ala11Gly	missense_variant	1/6	5
PRSS1	ENST00000485223.1	n.45C>G		non_coding_transcript_exon_variant	1/2	2
PRSS1	ENST00000497041.1	n.36C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 35790 AN: 105586 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.235

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.0145 AC: 17874 AN: 1234152 Hom.: 0 Cov.: 47 AF XY: 0.0149 AC XY: 9109 AN XY: 613026

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0330

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.0703

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0223

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.339 AC: 35824 AN: 105670 Hom.: 0 Cov.: 31 AF XY: 0.334 AC XY: 17375 AN XY: 52030

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.0993

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.329

Alfa AF: 0.357 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.15
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.010	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.60	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	3.3	N;.;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.20
MutPred		0.59		Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);
MVP		0.80
MPC		0.16
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.031
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs748442280; hg19: chr7-142457367;