chr12-55721281-A-G

Position:

chr12-55721281-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_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. 12/20 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.40

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 links:

BLOC1S1-RDH5 (HGNC:):

BLOC1S1-RDH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
RDH5	NM_002905.5 linkuse as main transcript	c.97A>G	p.Ile33Val	missense_variant	2/5	ENST00000257895.10	NP_002896.2
BLOC1S1-RDH5	NR_037658.1 linkuse as main transcript	n.370-408A>G		intron_variant, non_coding_transcript_variant
RDH5	NM_001199771.3 linkuse as main transcript	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 linkuse as main transcript	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.:

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

GnomAD3 exomes

AF:

0.00265

AC:

665

AN:

251068

Hom.:

AF XY:

0.00255

AC XY:

347

AN XY:

135824

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 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.:

Cov.:

AF XY:

0.00225

AC XY:

1636

AN XY:

727198

show subpopulations

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.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74478

show subpopulations

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.:

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

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

BayesDel_noAF

Benign

-0.090

CADD

Benign

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

MutationTaster

Benign

0.96

D;D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over