chr14-67722520-C-T

Variant names:

• chr14-67722520-C-T
• rs960563752
• NM_152443.3:c.-123C>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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
RDH12	NM_152443.3	c.-123C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 9	ENST00000551171.6	NP_689656.2
RDH12	NM_152443.3	c.-123C>T		5_prime_UTR_variant	Exon 3 of 9	ENST00000551171.6	NP_689656.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171	c.-123C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000551171	c.-123C>T		5_prime_UTR_variant	Exon 3 of 9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502	c.-123C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 8	5		ENSP00000267502.3
RDH12	ENST00000267502	c.-123C>T		5_prime_UTR_variant	Exon 2 of 8	5		ENSP00000267502.3

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152152 Hom.: 0 Cov.: 32

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

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

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis Pigmentosa, Recessive Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RDH12: PM3:Strong, PM2, BP2 -

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

Other links and lift over

dbSNP: rs960563752; hg19: chr14-68189237;