chr2-232523470-G-T

Variant names:

• chr2-232523470-G-T
• rs74703359
• NM_001195129.2:c.904G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 2.41
• Publications: 3 publications found

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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• nanophthalmia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Selected	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
	PRSS56	NM_001369848.1		c.904G>T	p.Val302Phe	missense	Exon 8 of 13	NP_001356777.1

Ensembl Transcripts

Selected	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
	PRSS56	ENST00000602410.1	TSL:2	n.*140G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152126 Hom.: 1 Cov.: 34

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

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.: 1 Cov.: 33 AF XY: 0.00178 AC XY: 1200 AN XY: 675036

African (AFR) AF: 0.0000638 AC: 2 AN: 31326

American (AMR) AF: 0.000409 AC: 14 AN: 34254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23934

East Asian (EAS) AF: 0.0000561 AC: 2 AN: 35628

South Asian (SAS) AF: 0.00115 AC: 88 AN: 76584

European-Finnish (FIN) AF: 0.000240 AC: 8 AN: 33384

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5554

European-Non Finnish (NFE) AF: 0.00214 AC: 2290 AN: 1072342

Other (OTH) AF: 0.00115 AC: 66 AN: 57306

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152244 Hom.: 1 Cov.: 34 AF XY: 0.00134 AC XY: 100 AN XY: 74466

African (AFR) AF: 0.000361 AC: 15 AN: 41556

American (AMR) AF: 0.00216 AC: 33 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 67982

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00138

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.000446 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Isolated microphthalmia 6 Pathogenic:1 Uncertain:1

Jan 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Benign	0.74
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.025	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.4
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.20	T
Vest4		0.91
MVP		0.61
GERP RS		3.9
Varity_R		0.33
gMVP		0.74
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs74703359; hg19: chr2-233388180;