rs267607006

Variant names:

• chr12-55724516-C-GAAG
• rs267607006
• NM_002905.5:c.928delCinsGAAG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_002905.5(RDH5):​c.928delCinsGAAG​(p.Leu310delinsGluVal) variant causes a missense, disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000617725: Functional studies have shown this variant results in reduced protein stability and activity levels as well as abnormal expression patterns (Lidén et al., 2001)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L310V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH5 NM_002905.5 missense, disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.904
• Publications: 1 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617725: Functional studies have shown this variant results in reduced protein stability and activity levels as well as abnormal expression patterns (Lidén et al., 2001).; SCV001413204: Experimental studies have shown that this variant affects RDH5 function (PMID: 11675386).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002905.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-55724516-C-GAAG is Pathogenic according to our data. Variant chr12-55724516-C-GAAG is described in ClinVar as Pathogenic. ClinVar VariationId is 8009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002905.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH5	NM_002905.5	MANE Select	c.928delCinsGAAG	p.Leu310delinsGluVal	missense disruptive_inframe_insertion	Exon 5 of 5	NP_002896.2	Q92781
	RDH5	NM_001199771.3		c.928delCinsGAAG	p.Leu310delinsGluVal	missense disruptive_inframe_insertion	Exon 5 of 5	NP_001186700.1	Q92781
	CD63	NM_001413284.1		c.*548delGinsCTTC		3_prime_UTR	Exon 9 of 9	NP_001400213.1	P08962-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH5	ENST00000257895.10	TSL:1 MANE Select	c.928delCinsGAAG	p.Leu310delinsGluVal	missense disruptive_inframe_insertion	Exon 5 of 5	ENSP00000257895.6	Q92781
	RDH5	ENST00000548082.1	TSL:1	c.928delCinsGAAG	p.Leu310delinsGluVal	missense disruptive_inframe_insertion	Exon 5 of 5	ENSP00000447128.1	Q92781
	ENSG00000258311	ENST00000550412.5	TSL:2	c.*2810delCinsGAAG		3_prime_UTR	Exon 4 of 4	ENSP00000447650.1	F8W036

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Fundus albipunctatus, autosomal recessive (1)
1	-	-	Pigmentary retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=13/187	disease causing

Splicing

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

Other links and lift over

dbSNP: rs267607006; hg19: chr12-56118300;