rs62638195

Variant names:

• chr12-55721281-A-G
• rs62638195
• NM_002905.5:c.97A>G
• RDH5 p.Ile33Val

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002905.5(RDH5):​c.97A>G​(p.Ile33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,100 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I33T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: RDH5 NM_002905.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.40
• Publications: 5 publications found

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]

RDH5 Gene-Disease associations (from GenCC):

• fundus albipunctatus

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• RDH5-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000258311 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010990709).
• BP6: Variant 12-55721281-A-G is Benign according to our data. Variant chr12-55721281-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258859.
• BS2: High Homozygotes in GnomAdExome4 at 11 SD,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002905.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH5	NM_002905.5	MANE Select	c.97A>G	p.Ile33Val	missense	Exon 2 of 5	NP_002896.2	Q92781
	RDH5	NM_001199771.3		c.97A>G	p.Ile33Val	missense	Exon 2 of 5	NP_001186700.1	Q92781
	BLOC1S1-RDH5	NR_037658.1		n.370-408A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH5	ENST00000257895.10	TSL:1 MANE Select	c.97A>G	p.Ile33Val	missense	Exon 2 of 5	ENSP00000257895.6	Q92781
	RDH5	ENST00000548082.1	TSL:1	c.97A>G	p.Ile33Val	missense	Exon 2 of 5	ENSP00000447128.1	Q92781
	ENSG00000258311	ENST00000550412.5	TSL:2	c.352-408A>G		intron	N/A	ENSP00000447650.1	F8W036

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00265 AC: 665 AN: 251068 AF XY: 0.00255

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00227 AC: 3323 AN: 1461786 Hom.: 11 Cov.: 32 AF XY: 0.00225 AC XY: 1636 AN XY: 727198

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.0195 AC: 1039 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00188 AC: 2086 AN: 1112010

Other (OTH) AF: 0.00215 AC: 130 AN: 60396

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74478

African (AFR) AF: 0.000216 AC: 9 AN: 41582

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00137 Hom.: 2

Bravo AF: 0.000979

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Pigmentary retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.047
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.47
Sift	Benign	0.048	D
Sift4G	Benign	0.10	T
Varity_R		0.19
gMVP		0.58
Mutation Taster		=98/2	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs62638195;

hg19: chr12-56115065;