rs74703359
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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
NM_001195129.2 missense
Scores
1
3
6
Clinical Significance
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]
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 10 pathogenic changes around while only 1 benign (91%) 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 | UniProt |
---|---|---|---|---|---|---|---|
PRSS56 | NM_001195129.2 | c.904G>T | p.Val302Phe | missense_variant | 8/13 | ENST00000617714.2 | |
PRSS56 | NM_001369848.1 | c.904G>T | p.Val302Phe | missense_variant | 8/13 | ||
PRSS56 | XM_047445431.1 | c.904G>T | p.Val302Phe | missense_variant | 8/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRSS56 | ENST00000617714.2 | c.904G>T | p.Val302Phe | missense_variant | 8/13 | 5 | NM_001195129.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00130 AC: 198AN: 152126Hom.: 1 Cov.: 34
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GnomAD3 exomes AF: 0.00103 AC: 125AN: 121702Hom.: 0 AF XY: 0.00117 AC XY: 77AN XY: 65764
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GnomAD4 exome AF: 0.00180 AC: 2471AN: 1370312Hom.: 1 Cov.: 33 AF XY: 0.00178 AC XY: 1200AN XY: 675036
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GnomAD4 genome ? AF: 0.00130 AC: 198AN: 152244Hom.: 1 Cov.: 34 AF XY: 0.00134 AC XY: 100AN XY: 74466
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | - - |
Isolated microphthalmia 6 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
PrimateAI
Uncertain
T
Sift4G
Benign
T;T
Vest4
MVP
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at