2-232523470-G-T

Position:

chr2-232523470-G-T

Variant summary

Our verdict is Likely benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain Peptidase S1 (size 232) in uniprot entity PRS56_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRSS56	NM_001195129.2 linkuse as main transcript	c.904G>T	p.Val302Phe	missense_variant	8/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1 linkuse as main transcript	c.904G>T	p.Val302Phe	missense_variant	8/13		NP_001356777.1
PRSS56	XM_047445431.1 linkuse as main transcript	c.904G>T	p.Val302Phe	missense_variant	8/12		XP_047301387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRSS56	ENST00000617714.2 linkuse as main transcript	c.904G>T	p.Val302Phe	missense_variant	8/13	5	NM_001195129.2	ENSP00000479745	P1

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

GnomAD3 exomes

AF:

0.00103

AC:

125

AN:

121702

Hom.:

AF XY:

0.00117

AC XY:

AN XY:

65764

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 SAS exome

AF:

0.00111

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

Gnomad4 AFR exome

AF:

0.0000638

Gnomad4 AMR exome

AF:

0.000409

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000561

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.000240

Gnomad4 NFE exome

AF:

0.00214

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152244

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.000945

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

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Isolated microphthalmia 6

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2021	This sequence change replaces valine with phenylalanine at codon 302 of the PRSS56 protein (p.Val302Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. While this variant is present in population databases (rs74703359), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with non-syndromic nanophthalmos (PMID: 21850159). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183171). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Benign

0.74

DEOGEN2

Benign

0.29

T;T

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.025

T;T

MutationAssessor

Benign

0.76

.;N

PrimateAI

Uncertain

0.68

Sift4G

Benign

0.20

T;T

Vest4

0.91

MVP

0.61

GERP RS

3.9

Varity_R

0.33

gMVP

0.74

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

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