19-10021436-C-T

Variant names:

• chr19-10021436-C-T
• NM_015725.4:c.718C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015725.4(RDH8):​c.718C>T​(p.Gln240*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RDH8 NM_015725.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.003794
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434
• Publications: 0 publications found

Genes affected

RDH8 (HGNC:14423): (retinol dehydrogenase 8) This gene encodes a member of the short-chain dehydrogenase/reductase family. The encoded protein catalyzes the reduction of all-trans-retinal to all-trans-retinol, the first reaction step of the rhodopsin regeneration pathway. This enzymatic reaction is the rate-limiting step in the visual cycle. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015725.4. 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
	RDH8	NM_015725.4	MANE Select	c.718C>T	p.Gln240*	stop_gained splice_region	Exon 5 of 6	NP_056540.3	Q9NYR8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH8	ENST00000591589.3	TSL:1 MANE Select	c.718C>T	p.Gln240*	stop_gained splice_region	Exon 5 of 6	ENSP00000466058.2	Q9NYR8
	RDH8	ENST00000651512.1		c.778C>T	p.Gln260*	stop_gained splice_region	Exon 5 of 6	ENSP00000498711.1	K7ELF7
	RDH8	ENST00000587782.1	TSL:2	c.162C>T	p.Phe54Phe	splice_region synonymous	Exon 2 of 3	ENSP00000465773.1	K7EKT5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.31	N
PhyloP100		0.43
Vest4		0.78
GERP RS		-0.23
Mutation Taster		=41/159	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0038
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.010		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

hg19: chr19-10132112;