Genetic Variant PRSS56:p.Val302Phe (chr2-232523470-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_001195129.2(PRSS56):c.904G>T(p.Val302Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,522,556 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0018 ( 1 hom. )

Consequence

PRSS56
NM_001195129.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 2.41

Publications

3 publications found

Variant links:

Genes affected

PRSS56 (HGNC:39433): (serine protease 56) This gene encodes a protein that contains a peptidase S1 domain and possesses trypsin-like serine protease activity. The encoded protein may play a role in eye development, and mutations in this gene are a cause of autosomal recessive posterior microphthalmos. [provided by RefSeq, Dec 2011]

PRSS56 Gene-Disease associations (from GenCC):

isolated microphthalmia 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
nanophthalmia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRSS56 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a domain Peptidase S1 (size 232) in uniprot entity PRS56_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001195129.2

BP4

Computational evidence support a benign effect (MetaRNN=0.02454713).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0013 (198/152244) while in subpopulation AMR AF = 0.00216 (33/15306). AF 95% confidence interval is 0.00179. There are 1 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195129.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	NM_001195129.2	MANE Select	c.904G>T	p.Val302Phe	missense	Exon 8 of 13	NP_001182058.1	P0CW18
	PRSS56	NM_001369848.1		c.904G>T	p.Val302Phe	missense	Exon 8 of 13	NP_001356777.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRSS56	ENST00000617714.2	TSL:5 MANE Select	c.904G>T	p.Val302Phe	missense	Exon 8 of 13	ENSP00000479745.1	P0CW18
	PRSS56	ENST00000602410.1	TSL:2	n.*140G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00103

AC:

125

AN:

121702

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000216

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000974

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.00192

Gnomad OTH exome

AF:

0.00106

GnomAD4 exome

AF:

0.00180

AC:

2471

AN:

1370312

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1200

AN XY:

675036

show subpopulations

African (AFR)

AF:

0.0000638

AC:

AN:

31326

American (AMR)

AF:

0.000409

AC:

AN:

34254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23934

East Asian (EAS)

AF:

0.0000561

AC:

AN:

35628

South Asian (SAS)

AF:

0.00115

AC:

AN:

76584

European-Finnish (FIN)

AF:

0.000240

AC:

AN:

33384

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00214

AC:

2290

AN:

1072342

Other (OTH)

AF:

0.00115

AC:

AN:

57306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

145

291

436

582

727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152244

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41556

American (AMR)

AF:

0.00216

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

67982

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.000446

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Isolated microphthalmia 6 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.60

MetaRNN

Benign

0.025

MutationAssessor

Benign

0.76

PhyloP100

2.4

PrimateAI

Uncertain

0.68

Sift4G

Benign

0.20

Vest4

0.91

MVP

0.61

GERP RS

3.9

Varity_R

0.33

gMVP

0.74

Mutation Taster

=38/62

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over