chr14-67722643-A-G

Position:

• chr14-67722643-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_152443.3(RDH12):​c.1A>G​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152443.3 (RDH12) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.1A>G	p.Met1?	start_lost	3/9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.1A>G	p.Met1?	start_lost	3/9		XP_047286921.1
GPHN	XM_047430879.1	c.1313-12552A>G		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.1A>G	p.Met1?	start_lost	3/9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.1A>G	p.Met1?	start_lost	2/8	5		ENSP00000267502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber congenital amaurosis 13 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Molecular and Cellular Biology, National Hospital Organization Tokyo Medical Center

Sep 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.31	T
PROVEAN	Benign	-0.14	N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.062	B;B
Vest4		0.79
MutPred		0.93		Gain of catalytic residue at M1 (P = 0.0443);Gain of catalytic residue at M1 (P = 0.0443);
MVP		0.90
ClinPred		0.52	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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: chr14-68189360;