rs104894373

chr12-55721908-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_002905.5(RDH5):c.530T>G(p.Val177Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,178 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RDH5 NM_002905.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.51

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]

BLOC1S1-RDH5 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Decreases androsterone dehydrogenase activity. (size 4) in uniprot entity RDH5_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002905.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 12-55721908-T-G is Pathogenic according to our data. Variant chr12-55721908-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 8007.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-55721908-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RDH5	NM_002905.5	c.530T>G	p.Val177Gly	missense_variant	3/5	ENST00000257895.10
BLOC1S1-RDH5	NR_037658.1	n.589T>G		non_coding_transcript_exon_variant	4/6
RDH5	NM_001199771.3	c.530T>G	p.Val177Gly	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH5	ENST00000257895.10	c.530T>G	p.Val177Gly	missense_variant	3/5	1	NM_002905.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247752 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461178 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fundus albipunctatus, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D;D
Eigen	Benign	0.046
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.77
MutPred		0.80		.;Gain of catalytic residue at K179 (P = 0);Gain of catalytic residue at K179 (P = 0);
MVP		0.99
MPC		0.61
ClinPred		0.86	D
GERP RS		4.2
Varity_R		0.70
gMVP		0.89

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: rs104894373; hg19: chr12-56115692;