14-67729193-ACCGGG-CCTCTTT

Position:

• chr14-67729193-ACCGGG-CCTCTTT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152443.3(RDH12):​c.661_666delACCGGGinsCCTCTTT​(p.Thr221fs) variant causes a frameshift, missense, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 frameshift, missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.94

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]

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 14-67729193-ACCGGG-CCTCTTT is Pathogenic according to our data. Variant chr14-67729193-ACCGGG-CCTCTTT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3576664.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.661_666delACCGGGinsCCTCTTT	p.Thr221fs	frameshift_variant, missense_variant, splice_region_variant	8/9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.661_666delACCGGGinsCCTCTTT	p.Thr221fs	frameshift_variant, missense_variant, splice_region_variant	8/9		XP_047286921.1
ZFYVE26	XM_047431173.1	c.*544_*549delCCCGGTinsAAAGAGG		3_prime_UTR_variant	42/42		XP_047287129.1
GPHN	XM_047430879.1	c.1313-6002_1313-5997delACCGGGinsCCTCTTT		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.661_666delACCGGGinsCCTCTTT	p.Thr221fs	frameshift_variant, missense_variant, splice_region_variant	8/9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.661_666delACCGGGinsCCTCTTT	p.Thr221fs	frameshift_variant, missense_variant, splice_region_variant	7/8	5		ENSP00000267502.3
RDH12	ENST00000552873.1	n.30_35delACCGGGinsCCTCTTT		splice_region_variant, non_coding_transcript_exon_variant	2/2	5
ZFYVE26	ENST00000394455.6	n.3288+13_3288+18delCCCGGTinsAAAGAGG		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-68195910;