rs104894473

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_152443.3(RDH12):​c.152T>A​(p.Ile51Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I51T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

RDH12
NM_152443.3 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 7.60
Variant links:
Genes affected
RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]
GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a binding_site (size 6) in uniprot entity RDH12_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_152443.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-67724556-T-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 14-67724556-T-A is Pathogenic according to our data. Variant chr14-67724556-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2057.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-67724556-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RDH12NM_152443.3 linkuse as main transcriptc.152T>A p.Ile51Asn missense_variant 4/9 ENST00000551171.6 NP_689656.2 Q96NR8A0A0S2Z613
RDH12XM_047430965.1 linkuse as main transcriptc.152T>A p.Ile51Asn missense_variant 4/9 XP_047286921.1
GPHNXM_047430879.1 linkuse as main transcriptc.1313-10639T>A intron_variant XP_047286835.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RDH12ENST00000551171.6 linkuse as main transcriptc.152T>A p.Ile51Asn missense_variant 4/91 NM_152443.3 ENSP00000449079.1 Q96NR8
RDH12ENST00000267502.3 linkuse as main transcriptc.152T>A p.Ile51Asn missense_variant 3/85 ENSP00000267502.3 Q96NR8

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2004- -
Pathogenic, no assertion criteria providedresearchLaboratory of Genetics in Ophthalmology, Institut Imagine-- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 01, 2022In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects RDH12 function (PMID: 20006610, 21232531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RDH12 protein function. ClinVar contains an entry for this variant (Variation ID: 2057). This missense change has been observed in individual(s) with autosomal recessive RDH12-related conditions (PMID: 15322982; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 51 of the RDH12 protein (p.Ile51Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;D
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.5
H;H
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.98
MutPred
0.92
Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.98
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894473; hg19: chr14-68191273; API