14-67722643-A-G

Position:

• chr14-67722643-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 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:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH12	ENST00000551171.6	c.1A>G	p.Met1?	start_lost	3/9	1	NM_152443.3	P1
RDH12	ENST00000267502.3	c.1A>G	p.Met1?	start_lost	2/8	5		P1

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
MutationTaster	Benign	0.99	D;D;D
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;