rs111033593
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate
The NM_002905.5(RDH5):āc.880G>Cā(p.Ala294Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,832 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 (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000027 ( 0 hom. )
Consequence
RDH5
NM_002905.5 missense
NM_002905.5 missense
Scores
4
10
4
Clinical Significance
Conservation
PhyloP100: 0.134
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a transmembrane_region Helical (size 20) in uniprot entity RDH5_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002905.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.804
PP5
?
Variant 12-55724468-G-C is Pathogenic according to our data. Variant chr12-55724468-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 8006.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-55724468-G-C is described in Lovd as [Pathogenic]. Variant chr12-55724468-G-C is described in Lovd as [Likely_pathogenic]. Variant chr12-55724468-G-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDH5 | NM_002905.5 | c.880G>C | p.Ala294Pro | missense_variant | 5/5 | ENST00000257895.10 | |
BLOC1S1-RDH5 | NR_037658.1 | n.939G>C | non_coding_transcript_exon_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDH5 | ENST00000257895.10 | c.880G>C | p.Ala294Pro | missense_variant | 5/5 | 1 | NM_002905.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251176Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135806
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461656Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727156
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pigmentary retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Fundus albipunctatus, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 30, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RDH5 function (PMID: 11675386). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 8006). This missense change has been observed in individual(s) with fundus albipunctatus (PMID: 10617778, 20829743). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 294 of the RDH5 protein (p.Ala294Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.99
.;D;D
Vest4
MVP
MPC
0.45
ClinPred
D
GERP RS
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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