7-142749500-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002769.5(PRSS1):c.16A>T(p.Ile6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I6V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PRSS1 NM_002769.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.718

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16470423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRSS1	NM_002769.5	c.16A>T	p.Ile6Phe	missense_variant	1/5	ENST00000311737.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRSS1	ENST00000311737.12	c.16A>T	p.Ile6Phe	missense_variant	1/5	1	NM_002769.5	P1
PRSS1	ENST00000486171.5	c.16A>T	p.Ile6Phe	missense_variant	1/6	5
PRSS1	ENST00000485223.1	n.29A>T		non_coding_transcript_exon_variant	1/2	2
PRSS1	ENST00000497041.1	n.20A>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 34

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 13, 2021	The p.I6F variant (also known as c.16A>T), located in coding exon 1 of the PRSS1 gene, results from an A to T substitution at nucleotide position 16. The isoleucine at codon 6 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 23, 2020	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. 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 phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PRSS1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 6 of the PRSS1 protein (p.Ile6Phe). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	13
Dann	Benign	0.20
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.59	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.56	N;.;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0020	.;.;B
Vest4		0.27
MutPred		0.54		Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);
MVP		0.79
MPC		0.26
ClinPred		0.17	T
GERP RS		0.65
Varity_R		0.039
gMVP		0.64

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: rs1585972378; hg19: chr7-142457351;