rs774122562
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002905.5(RDH5):c.285G>A(p.Trp95*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000343 in 1,458,464 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
RDH5
NM_002905.5 stop_gained
NM_002905.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.90
Genes affected
RDH5 (HGNC:9940): (retinol dehydrogenase 5) This gene encodes an enzyme belonging to the short-chain dehydrogenases/reductases (SDR) family. This retinol dehydrogenase functions to catalyze the final step in the biosynthesis of 11-cis retinaldehyde, which is the universal chromophore of visual pigments. Mutations in this gene cause autosomal recessive fundus albipunctatus, a rare form of night blindness that is characterized by a delay in the regeneration of cone and rod photopigments. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S1 (biogenesis of lysosomal organelles complex-1, subunit 1) gene. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-55721469-G-A is Pathogenic according to our data. Variant chr12-55721469-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-55721469-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RDH5 | NM_002905.5 | c.285G>A | p.Trp95* | stop_gained | 2/5 | ENST00000257895.10 | NP_002896.2 | |
RDH5 | NM_001199771.3 | c.285G>A | p.Trp95* | stop_gained | 2/5 | NP_001186700.1 | ||
BLOC1S1-RDH5 | NR_037658.1 | n.370-220G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RDH5 | ENST00000257895.10 | c.285G>A | p.Trp95* | stop_gained | 2/5 | 1 | NM_002905.5 | ENSP00000257895.6 | ||
ENSG00000258311 | ENST00000550412.5 | c.352-220G>A | intron_variant | 2 | ENSP00000447650.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000282 AC: 7AN: 247944Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134432
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458464Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725778
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pigmentary retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 30, 2014 | The Trp95X variant in RDH5 has been reported in 1 compound heterozygous Asian individual with fundus albipunctatus (Wang 2012). This variant has also been identified in 3/8708 of East Asian chromosomes by the Exome aggregation Consortium (http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 95, which is predicted to lead to a truncated or absent protein. Complete loss of RDH5 function is an established disease mechanism for fundus albipunctatus (Driessen 2001, Schatz 2010, Sergouniotis 2011). In summary, this variant meets our criteria to be classified as pathogenic for fundus albipunctatus in an autosomal recessive manner based on the predicted impact to the protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PM2_Supporting+PP4 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2017 | The W95X variant has been reported previously in association with fundus albipunctatus (Wang et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 208608). This premature translational stop signal has been observed in individual(s) with fundus albipunctatus (PMID: 22669287). This variant is present in population databases (rs774122562, gnomAD 0.04%). This sequence change creates a premature translational stop signal (p.Trp95*) in the RDH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH5 are known to be pathogenic (PMID: 11675386, 22815624). - |
Fundus albipunctatus, autosomal recessive Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as pathogenic and reported on 12/30/2014 by GTR ID 21766. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at