chr14-67722520-C-T

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

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.425
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]

Genome browser will be placed here

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
RDH12NM_152443.3 linkuse as main transcriptc.-123C>T 5_prime_UTR_variant 3/9 ENST00000551171.6
RDH12XM_047430965.1 linkuse as main transcriptc.-123C>T 5_prime_UTR_variant 3/9
GPHNXM_047430879.1 linkuse as main transcriptc.1313-12675C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RDH12ENST00000551171.6 linkuse as main transcriptc.-123C>T 5_prime_UTR_variant 3/91 NM_152443.3 P1
RDH12ENST00000267502.3 linkuse as main transcriptc.-123C>T 5_prime_UTR_variant 2/85 P1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00144
GnomAD4 exome
AF:
0.0000622
AC:
42
AN:
675050
Hom.:
0
Cov.:
8
AF XY:
0.0000740
AC XY:
27
AN XY:
365040
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000573
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000277
Gnomad4 SAS exome
AF:
0.0000285
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000329
Gnomad4 OTH exome
AF:
0.0000290
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00144
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000756

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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 30, 2024Variant 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
9.2
DANN
Benign
0.68

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: rs960563752; hg19: chr14-68189237; API