12-55721245-C-T

Variant names:

• chr12-55721245-C-T
• rs749791034
• NM_002905.5:c.61C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002905.5(RDH5):​c.61C>T​(p.Arg21Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RDH5 NM_002905.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25761822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH5	NM_002905.5	c.61C>T	p.Arg21Trp	missense_variant	Exon 2 of 5	ENST00000257895.10	NP_002896.2
RDH5	NM_001199771.3	c.61C>T	p.Arg21Trp	missense_variant	Exon 2 of 5		NP_001186700.1
BLOC1S1-RDH5	NR_037658.1	n.370-444C>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.61C>T	p.Arg21Trp	missense_variant	Exon 2 of 5	1	NM_002905.5	ENSP00000257895.6
ENSG00000258311	ENST00000550412.5	c.352-444C>T		intron_variant	Intron 3 of 3	2		ENSP00000447650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250770 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.40	B;B
Vest4		0.23
MutPred		0.56		Gain of catalytic residue at W16 (P = 0.0068);Gain of catalytic residue at W16 (P = 0.0068);
MVP		0.72
MPC		0.18
ClinPred		0.66	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.61

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: rs749791034; hg19: chr12-56115029;