Genetic Variant PRSS58:p.Val64Met (chr7-142255301-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_001001317.5(PRSS58):c.190G>A(p.Val64Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRSS58
NM_001001317.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

1 publications found

Variant links:

Genes affected

PRSS58 (HGNC:39125): (serine protease 58) This gene encodes a member of the trypsin family of serine proteases. This gene and several related trypsinogen genes are localized to the T cell receptor beta locus on chromosome 7. This gene was previously described as a trypsinogen-like pseudogene, but it is now thought to be a protein-coding gene. [provided by RefSeq, Jul 2008]

PRSS58 links:

ENSG00000241881 (HGNC:):

ENSG00000241881 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
PRSS58	NM_001001317.5 link	c.190G>A	p.Val64Met	missense_variant	Exon 4 of 6	ENST00000547058.6	NP_001001317.1	Q8IYP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRSS58	ENST00000547058.6 link	c.190G>A	p.Val64Met	missense_variant	Exon 4 of 6	1	NM_001001317.5	ENSP00000447588.2	Q8IYP2
PRSS58	ENST00000552471.1 link	c.190G>A	p.Val64Met	missense_variant	Exon 3 of 5	2		ENSP00000446916.1	Q8IYP2
ENSG00000241881	ENST00000486508.2 link	n.254+6518C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250702

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461418

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.0000447

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111660

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.190G>A (p.V64M) alteration is located in exon 4 (coding exon 3) of the PRSS58 gene. This alteration results from a G to A substitution at nucleotide position 190, causing the valine (V) at amino acid position 64 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

0.44

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;D

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

-0.10

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

2.5

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.92

P;P

Vest4

0.36

MutPred

0.66

Loss of catalytic residue at V64 (P = 0.0715);Loss of catalytic residue at V64 (P = 0.0715);

MVP

0.68

MPC

0.23

ClinPred

0.92

GERP RS

1.7

Varity_R

0.063

gMVP

0.46

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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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7-142255301-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over