rs786205148
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001164688.2(RD3):c.112C>T(p.Arg38Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000821 in 1,461,870 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
RD3
NM_001164688.2 stop_gained
NM_001164688.2 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.10
Genes affected
RD3 (HGNC:19689): (RD3 regulator of GUCY2D) This gene encodes a retinal protein that is associated with promyelocytic leukemia-gene product (PML) bodies in the nucleus. Mutations in this gene cause Leber congenital amaurosis type 12, a disease that results in retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-211481304-G-A is Pathogenic according to our data. Variant chr1-211481304-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-211481304-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RD3 | NM_001164688.2 | c.112C>T | p.Arg38Ter | stop_gained | 2/3 | ENST00000680073.1 | |
RD3 | NM_183059.3 | c.112C>T | p.Arg38Ter | stop_gained | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RD3 | ENST00000680073.1 | c.112C>T | p.Arg38Ter | stop_gained | 2/3 | NM_001164688.2 | P1 | ||
RD3 | ENST00000367002.5 | c.112C>T | p.Arg38Ter | stop_gained | 2/3 | 1 | P1 | ||
RD3 | ENST00000484910.1 | n.265-1977C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135828
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727242
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leber congenital amaurosis 12 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Arg38*) in the RD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RD3 are known to be pathogenic (PMID: 23308101). This variant is present in population databases (rs786205148, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 23308101). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189792). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2013 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
RD3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2023 | The RD3 c.112C>T variant is predicted to result in premature protein termination (p.Arg38*). This variant has been reported in the homozygous state multiple individuals with Leber congenital amaurosis (Perrault et al 2013. PubMed ID: 23308101; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in RD3 are expected to be pathogenic. Given all the evidence, we interpret this variant as pathogenic. - |
Abnormality of the eye Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
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