rs74703359

Positions:

• chr2-232523470-G-T

Variant summary

Our verdict is Likely benign. Variant got -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

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]

ACMG classification

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	UniProt
PRSS56	NM_001195129.2	c.904G>T	p.Val302Phe	missense_variant	8/13	ENST00000617714.2	NP_001182058.1
PRSS56	NM_001369848.1	c.904G>T	p.Val302Phe	missense_variant	8/13		NP_001356777.1
PRSS56	XM_047445431.1	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	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.: 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

GnomAD3 exomes AF: 0.00103 AC: 125 AN: 121702 Hom.: 0 AF XY: 0.00117 AC XY: 77 AN XY: 65764

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

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.: 1 Cov.: 34 AF XY: 0.00134 AC XY: 100 AN XY: 74466

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.: 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

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:1 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Benign	0.74
DEOGEN2	Benign	0.29	T;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.025	T;T
MutationAssessor	Benign	0.76	.;N
PrimateAI	Uncertain	0.68	T
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

Other links and lift over

dbSNP: rs74703359; hg19: chr2-233388180;