chr12-55721281-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.40

Publications

5 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
RDH5-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

RDH5 links:

ENSG00000258311 (HGNC:):

ENSG00000258311 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH5	NM_002905.5 link	c.97A>G	p.Ile33Val	missense_variant	Exon 2 of 5	ENST00000257895.10	NP_002896.2	Q92781A0A024RB18
RDH5	NM_001199771.3 link	c.97A>G	p.Ile33Val	missense_variant	Exon 2 of 5		NP_001186700.1	Q92781A0A024RB18
BLOC1S1-RDH5	NR_037658.1 link	n.370-408A>G		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10 link	c.97A>G	p.Ile33Val	missense_variant	Exon 2 of 5	1	NM_002905.5	ENSP00000257895.6		Q92781
ENSG00000258311	ENST00000550412.5 link	c.352-408A>G		intron_variant	Intron 3 of 3	2		ENSP00000447650.1		F8W036

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

376

AN:

152196

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00225

AC XY:

1636

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000693

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0195

AC:

1039

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00188

AC:

2086

AN:

1112010

Other (OTH)

AF:

0.00215

AC:

130

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00247

AC:

376

AN:

152314

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41582

American (AMR)

AF:

0.000915

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0231

AC:

245

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00150

AC:

102

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.000979

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00218

AC:

265

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pigmentary retinal dystrophy

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.047

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.83

.;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

-0.078

MutationAssessor

Benign

1.2

L;L

PhyloP100

2.4

PrimateAI

Uncertain

0.50

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

GERP RS

3.9

Varity_R

0.19

gMVP

0.58

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over