chr14-67722520-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_152443.3(RDH12):c.-123C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000665 in 827,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )
Consequence
RDH12
NM_152443.3 5_prime_UTR
NM_152443.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.425
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDH12 | NM_152443.3 | c.-123C>T | 5_prime_UTR_variant | 3/9 | ENST00000551171.6 | ||
RDH12 | XM_047430965.1 | c.-123C>T | 5_prime_UTR_variant | 3/9 | |||
GPHN | XM_047430879.1 | c.1313-12675C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDH12 | ENST00000551171.6 | c.-123C>T | 5_prime_UTR_variant | 3/9 | 1 | NM_152443.3 | P1 | ||
RDH12 | ENST00000267502.3 | c.-123C>T | 5_prime_UTR_variant | 2/8 | 5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152152Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000622 AC: 42AN: 675050Hom.: 0 Cov.: 8 AF XY: 0.0000740 AC XY: 27AN XY: 365040
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis Pigmentosa, Recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2024 | Variant summary: RDH12 c.-123C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 6.6e-05 in 827202 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (6.6e-05 vs 0.0016), allowing no conclusion about variant significance. c.-123C>T has been reported in the literature in homoyzgous or compound heterozygous individuals affected with Leber Congenital Amaurosis (Daich Varela_2024, Duenas Rey_2024). However, the variant is frequently found in cis with c.701G>A (p.Arg234His) (Variation ID: 313842). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. At least one publication reports experimental evidence evaluating an impact on protein function. Using a dual luciferase assay in ARPE-19 cells, the variant was shown to impact protein translation (Duenas Rey_2024). The following publications have been ascertained in the context of this evaluation (PMID: 37714431, 38184646). ClinVar contains an entry for this variant (Variation ID: 884100). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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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