10-47349328-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002900.3(RBP3):c.844G>A(p.Val282Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,612,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
RBP3
NM_002900.3 missense
NM_002900.3 missense
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 4.30
Genes affected
RBP3 (HGNC:9921): (retinol binding protein 3) Interphotoreceptor retinol-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process.The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.765
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RBP3 | NM_002900.3 | c.844G>A | p.Val282Met | missense_variant | 1/4 | ENST00000584701.2 | NP_002891.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RBP3 | ENST00000584701.2 | c.844G>A | p.Val282Met | missense_variant | 1/4 | 1 | NM_002900.3 | ENSP00000463151 | P1 |
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000328 AC: 8AN: 243746Hom.: 0 AF XY: 0.0000377 AC XY: 5AN XY: 132738
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GnomAD4 exome AF: 0.0000452 AC: 66AN: 1460310Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 726444
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GnomAD4 genome 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 04, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 282 of the RBP3 protein (p.Val282Met). 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 208298). This variant has not been reported in the literature in individuals affected with RBP3-related conditions. This variant is present in population databases (rs782095820, gnomAD 0.01%). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2022 | - - |
Retinitis pigmentosa 66 Uncertain:1
| Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 27, 2013 | - - |
Computational scores
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Name
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AlphaMissense
Benign
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
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LIST_S2
Uncertain
D
MetaRNN
Pathogenic
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Sift4G
Uncertain
D
Vest4
gMVP
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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