Genetic Variant PRSS58:p.Asp150Asn (chr7-142252600-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001001317.5(PRSS58):c.448G>A(p.Asp150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,611,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

PRSS58
NM_001001317.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.625

Publications

3 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032891005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRSS58	NM_001001317.5 link	c.448G>A	p.Asp150Asn	missense_variant	Exon 5 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.448G>A	p.Asp150Asn	missense_variant	Exon 5 of 6	1	NM_001001317.5	ENSP00000447588.2	Q8IYP2
PRSS58	ENST00000552471.1 link	c.448G>A	p.Asp150Asn	missense_variant	Exon 4 of 5	2		ENSP00000446916.1	Q8IYP2
ENSG00000241881	ENST00000486508.2 link	n.254+3817C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000229

AC:

AN:

248552

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000273

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.000355

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000370

AC:

540

AN:

1459398

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

240

AN XY:

725806

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33336

American (AMR)

AF:

0.000113

AC:

AN:

44100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000446

AC:

496

AN:

1111486

Other (OTH)

AF:

0.000431

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000302

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41420

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.448G>A (p.D150N) alteration is located in exon 5 (coding exon 4) of the PRSS58 gene. This alteration results from a G to A substitution at nucleotide position 448, causing the aspartic acid (D) at amino acid position 150 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.29

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.033

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.63

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.27

Sift

Benign

0.19

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.93

P;P

Vest4

0.26

MVP

0.57

MPC

0.040

ClinPred

0.035

GERP RS

0.84

Varity_R

0.067

gMVP

0.41

Mutation Taster

=92/8

polymorphism

(source)

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

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chr7-142252600-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