chr14-67729195-C-A

Position:

• chr14-67729195-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152443.3(RDH12):​c.663C>A​(p.Thr221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T221T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.64

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RDH12	NM_152443.3	c.663C>A	p.Thr221=	synonymous_variant	8/9	ENST00000551171.6
RDH12	XM_047430965.1	c.663C>A	p.Thr221=	synonymous_variant	8/9
ZFYVE26	XM_047431173.1	c.*547G>T		3_prime_UTR_variant	42/42
GPHN	XM_047430879.1	c.1313-6000C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH12	ENST00000551171.6	c.663C>A	p.Thr221=	synonymous_variant	8/9	1	NM_152443.3	P1
RDH12	ENST00000267502.3	c.663C>A	p.Thr221=	synonymous_variant	7/8	5		P1
RDH12	ENST00000552873.1	n.32C>A		non_coding_transcript_exon_variant	2/2	5
ZFYVE26	ENST00000394455.6	n.3288+16G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with RDH12-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 221 of the RDH12 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RDH12 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.63		Position offset: 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: chr14-68195912;