Genetic Variant PRSS33:p.Val248Met (chr16-2784745-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152891.3(PRSS33):c.742G>A(p.Val248Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,608,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PRSS33
NM_152891.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Publications

0 publications found

Variant links:

Genes affected

PRSS33 (HGNC:30405): (serine protease 33) Enables serine-type endopeptidase activity. Involved in protein kinase C signaling and proteolysis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PRSS33 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
PRSS33	NM_152891.3 link	c.742G>A	p.Val248Met	missense_variant	Exon 7 of 7	ENST00000682474.1	NP_690851.2	Q8NF86

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRSS33	ENST00000682474.1 link	c.742G>A	p.Val248Met	missense_variant	Exon 7 of 7		NM_152891.3	ENSP00000507560.1		Q8NF86

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000212

AC:

AN:

235330

AF XY:

0.0000312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000888

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000952

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1456148

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

723854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33344

American (AMR)

AF:

0.0000904

AC:

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1109668

Other (OTH)

AF:

0.0000499

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41560

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.742G>A (p.V248M) alteration is located in exon 6 (coding exon 6) of the PRSS33 gene. This alteration results from a G to A substitution at nucleotide position 742, causing the valine (V) at amino acid position 248 to be replaced by a methionine (M). 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

Uncertain

0.38

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

0.75

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.2

N;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.57

MutPred

0.66

Loss of catalytic residue at V248 (P = 0.0107);Loss of catalytic residue at V248 (P = 0.0107);

MVP

0.77

MPC

1.1

ClinPred

0.58

GERP RS

4.7

Varity_R

0.14

gMVP

0.63

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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16-2784745-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over