rs116733939

Variant names:

• chr14-67727056-C-A
• rs116733939
• NM_152443.3:c.524C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-67727056-C-A
• chr14-67727056-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152443.3(RDH12):​c.524C>A​(p.Ser175*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S175S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-67727056-C-A is Pathogenic according to our data. Variant chr14-67727056-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1076205.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3	c.524C>A	p.Ser175*	stop_gained	Exon 7 of 9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.524C>A	p.Ser175*	stop_gained	Exon 7 of 9		XP_047286921.1
GPHN	XM_047430879.1	c.1313-8139C>A		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.524C>A	p.Ser175*	stop_gained	Exon 7 of 9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.524C>A	p.Ser175*	stop_gained	Exon 6 of 8	5		ENSP00000267502.3
RDH12	ENST00000552873.1	n.-108C>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:1

May 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with RDH12-related conditions. This sequence change creates a premature translational stop signal (p.Ser175*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.9
Vest4		0.93
GERP RS		5.8
Mutation Taster		=49/151	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 2

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

Other links and lift over

dbSNP: rs116733939; hg19: chr14-68193773;