12-55723916-C-G

Position:

• chr12-55723916-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002905.5(RDH5):​c.600C>G​(p.Val200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0523 in 1,613,962 control chromosomes in the GnomAD database, including 6,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V200V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (2700 hom., cov: 32)
  • Exomes 𝑓: 0.044 (4087 hom.)
• Consequence: RDH5 NM_002905.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.945

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]

BLOC1S1-RDH5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-55723916-C-G is Benign according to our data. Variant chr12-55723916-C-G is described in ClinVar as [Benign]. Clinvar id is 258858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.945 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH5	NM_002905.5	c.600C>G	p.Val200=	synonymous_variant	4/5	ENST00000257895.10	NP_002896.2
BLOC1S1-RDH5	NR_037658.1	n.659C>G		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.600C>G	p.Val200=	synonymous_variant	4/5	1	NM_002905.5	ENSP00000257895	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19905 AN: 152126 Hom.: 2693 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.0662

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0821 AC: 20639 AN: 251260 Hom.: 2072 AF XY: 0.0713 AC XY: 9690 AN XY: 135828

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.0647

Gnomad EAS exome AF: 0.0265

Gnomad SAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0441 AC: 64532 AN: 1461718 Hom.: 4087 Cov.: 31 AF XY: 0.0431 AC XY: 31349 AN XY: 727174

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.209

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.0631

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0593

GnomAD4 genome AF: 0.131 AC: 19936 AN: 152244 Hom.: 2700 Cov.: 32 AF XY: 0.130 AC XY: 9708 AN XY: 74458

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.0662

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0617

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0316 Hom.: 51

Bravo AF: 0.151

Asia WGS AF: 0.0580 AC: 204 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0303

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Pigmentary retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.9
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13193; hg19: chr12-56117700;