rs794729650

Positions:

chr14-67722698-CTCCA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_152443.3(RDH12):c.63_66delCATC(p.Ile22fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000744 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RDH12
NM_152443.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.25

Variant links:

Genes affected

RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]

RDH12 links:

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 156 pathogenic variants in the truncated region.

PP5

Variant 14-67722698-CTCCA-C is Pathogenic according to our data. Variant chr14-67722698-CTCCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67722698-CTCCA-C is described in Lovd as [Pathogenic]. Variant chr14-67722698-CTCCA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3 linkuse as main transcript	c.63_66delCATC	p.Ile22fs	frameshift_variant, splice_region_variant	3/9	ENST00000551171.6	NP_689656.2	Q96NR8A0A0S2Z613
RDH12	XM_047430965.1 linkuse as main transcript	c.63_66delCATC	p.Ile22fs	frameshift_variant, splice_region_variant	3/9		XP_047286921.1
GPHN	XM_047430879.1 linkuse as main transcript	c.1313-12490_1313-12487delCATC		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6 linkuse as main transcript	c.63_66delCATC	p.Ile22fs	frameshift_variant, splice_region_variant	3/9	1	NM_152443.3	ENSP00000449079.1		Q96NR8
RDH12	ENST00000267502.3 linkuse as main transcript	c.63_66delCATC	p.Ile22fs	frameshift_variant, splice_region_variant	2/8	5		ENSP00000267502.3		Q96NR8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461294

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 29, 2023	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 17, 2015	This variant (c.63_66del; p.Ile22Glyfs*19) has been previously published in a cohort with LCA in one individual (PMID: 17964524) and results in a premature stop 19 amino acids later. The resulting product being severely truncated and less than 1/3 of the expected length. This variant is not seen in the ExAC database nor in the ClinVar database. -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2023	For these reasons, this variant has been classified as Pathogenic. This variant is also known as Ile22Gly. This premature translational stop signal has been observed in individual(s) with autosomal recessive early onset retinal disease (PMID: 30372751). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile22Glyfs*19) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17964524, 30372751, 22065924, 36284670, 24154662) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2017	- -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over