7-142749506-A-G

Position:

• chr7-142749506-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BS1 BS2_Supporting

The NM_002769.5(PRSS1):​c.22A>G​(p.Thr8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,242,132 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 (★).

• Frequency:
  • Genomes: 𝑓 0.33 (0 hom., cov: 31)
  • Exomes 𝑓: 0.013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

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]

TRB (HGNC:12155):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06721094).
• BP6: Variant 7-142749506-A-G is Benign according to our data. Variant chr7-142749506-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1789246.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 = 0.0132 (16395/1242132) while in subpopulation AFR AF= 0.0249 (651/26158). AF 95% confidence interval is 0.0233. There are 0 homozygotes in gnomad4_exome. There are 8400 alleles in male gnomad4_exome subpopulation. Median coverage is 48. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 16395 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/exons	MANE	Protein	UniProt
PRSS1	NM_002769.5	c.22A>G	p.Thr8Ala	missense_variant	1/5	ENST00000311737.12	NP_002760.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS1	ENST00000311737.12	c.22A>G	p.Thr8Ala	missense_variant	1/5	1	NM_002769.5	ENSP00000308720.7
PRSS1	ENST00000486171.5	c.22A>G	p.Thr8Ala	missense_variant	1/6	5		ENSP00000417854.1
PRSS1	ENST00000485223.1	n.35A>G		non_coding_transcript_exon_variant	1/2	2
PRSS1	ENST00000497041.1	n.26A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 34677 AN: 105182 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.198

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.328

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0132 AC: 16395 AN: 1242132 Hom.: 0 Cov.: 48 AF XY: 0.0136 AC XY: 8400 AN XY: 616696

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.0123

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.0672

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.330 AC: 34703 AN: 105258 Hom.: 0 Cov.: 31 AF XY: 0.325 AC XY: 16818 AN XY: 51734

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.0917

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.323

Alfa AF: 0.360 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

Apr 01, 2022

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	0.062
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.2
DANN	Benign	0.12
DEOGEN2	Benign	0.18	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0039	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-1.1	.;.;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.1	N;.;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.14
MutPred		0.46		Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);
MVP		0.63
MPC		0.16
ClinPred		0.044	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.60

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: rs749856663; hg19: chr7-142457357;