Genetic Variant PRSS22:p.Ala76Thr (chr16-2856137-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_022119.4(PRSS22):c.226G>A(p.Ala76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PRSS22
NM_022119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.52

Variant links:

Genes affected

PRSS22 (HGNC:14368): (serine protease 22) This gene encodes a member of the trypsin family of serine proteases. The enzyme is expressed in the airways in a developmentally regulated manner. The gene is part of a cluster of serine protease genes on chromosome 16. [provided by RefSeq, Jul 2008]

PRSS22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS22	NM_022119.4 link	c.226G>A	p.Ala76Thr	missense_variant	Exon 3 of 6	ENST00000161006.8	NP_071402.1	Q9GZN4
PRSS22	XM_047434451.1 link	c.-218G>A		5_prime_UTR_variant	Exon 2 of 4		XP_047290407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS22	ENST00000161006.8 link	c.226G>A	p.Ala76Thr	missense_variant	Exon 3 of 6	1	NM_022119.4	ENSP00000161006.3		Q9GZN4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251350

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226G>A (p.A76T) alteration is located in exon 3 (coding exon 3) of the PRSS22 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the alanine (A) at amino acid position 76 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.60

D;T

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

0.48

N;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.0050

D;T

Polyphen

0.99

D;.

Vest4

0.51

MVP

0.86

MPC

0.98

ClinPred

0.65

GERP RS

4.9

Varity_R

0.18

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over