12-55721847-C-T

Position:

chr12-55721847-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002905.5(RDH5):c.469C>T(p.Arg157Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RDH5
NM_002905.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.72

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:

ENSG00000258311 (HGNC:):

ENSG00000258311 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-55721848-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 12-55721847-C-T is Pathogenic according to our data. Variant chr12-55721847-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-55721847-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-55721847-C-T is described in Lovd as [Pathogenic]. Variant chr12-55721847-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH5	NM_002905.5 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	3/5	ENST00000257895.10	NP_002896.2	Q92781A0A024RB18
RDH5	NM_001199771.3 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	3/5		NP_001186700.1	Q92781A0A024RB18
BLOC1S1-RDH5	NR_037658.1 linkuse as main transcript	n.528C>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10 linkuse as main transcript	c.469C>T	p.Arg157Trp	missense_variant	3/5	1	NM_002905.5	ENSP00000257895.6		Q92781
ENSG00000258311	ENST00000550412.5 linkuse as main transcript	c.*141C>T		3_prime_UTR_variant	4/4	2		ENSP00000447650.1		F8W036

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249444

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pigmentary retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Fundus albipunctatus, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 157 of the RDH5 protein (p.Arg157Trp). This variant is present in population databases (rs104894374, gnomAD 0.02%). This missense change has been observed in individuals with fundus albipunctatus (PMID: 11153648, 14991316; Invitae). ClinVar contains an entry for this variant (Variation ID: 8010). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RDH5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RDH5 function (PMID: 11153648, 11675386). This variant disrupts the p.Arg157 amino acid residue in RDH5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18949499, 21529959). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

.;H;H

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.87

MVP

0.99

MPC

0.61

ClinPred

0.99

GERP RS

3.5

Varity_R

0.88

gMVP

0.95

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