rs62638195

Positions:

• chr12-55721281-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 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. 12/20 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. I33N) has been classified as Likely pathogenic.

• 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

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a topological_domain Lumenal (size 266) in uniprot entity RDH5_HUMAN there are 57 pathogenic changes around while only 2 benign (97%) in NM_002905.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-55721282-T-A is described in Lovd as [Likely_pathogenic].
• 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 id is 258859.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr12-55721281-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH5	NM_002905.5	c.97A>G	p.Ile33Val	missense_variant	2/5	ENST00000257895.10	NP_002896.2
BLOC1S1-RDH5	NR_037658.1	n.370-408A>G		intron_variant, non_coding_transcript_variant
RDH5	NM_001199771.3	c.97A>G	p.Ile33Val	missense_variant	2/5		NP_001186700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.97A>G	p.Ile33Val	missense_variant	2/5	1	NM_002905.5	ENSP00000257895	P1

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

GnomAD3 exomes AF: 0.00265 AC: 665 AN: 251068 Hom.: 1 AF XY: 0.00255 AC XY: 347 AN XY: 135824

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 SAS exome AF: 0.000392

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

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00215

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

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000979

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00218 AC: 265

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pigmentary retinal dystrophy Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.86	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.048	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.72	P;P
Vest4		0.26
MVP		0.85
MPC		0.15
ClinPred		0.036	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.58

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: rs62638195; hg19: chr12-56115065;