rs62638191

Variant names:

• chr12-55724028-G-A
• rs62638191
• NM_002905.5:c.712G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-55724028-G-A
• chr12-55724028-G-C
• chr12-55724028-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_002905.5(RDH5):​c.712G>A​(p.Gly238Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G238W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH5 NM_002905.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97
• Publications: 16 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]

ENSG00000258311 (HGNC:):

CD63 (HGNC:1692): (CD63 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-55724028-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH5	NM_002905.5	c.712G>A	p.Gly238Arg	missense_variant	Exon 4 of 5	ENST00000257895.10	NP_002896.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.712G>A	p.Gly238Arg	missense_variant	Exon 4 of 5	1	NM_002905.5	ENSP00000257895.6
ENSG00000258311	ENST00000550412.5	c.*2322G>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000447650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.096	T;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.7	.;H;H
PhyloP100		10
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.90
MutPred		0.64		.;Gain of methylation at G238 (P = 0.0114);Gain of methylation at G238 (P = 0.0114);
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.93
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62638191; hg19: chr12-56117812;