rs769317754

Variant names:

• chr14-67729194-C-A
• rs769317754
• NM_152443.3:c.662C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-67729194-C-A
• chr14-67729194-C-T

Variant summary

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

The NM_152443.3(RDH12):​c.662C>A​(p.Thr221Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3	c.662C>A	p.Thr221Asn	missense_variant	Exon 8 of 9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.662C>A	p.Thr221Asn	missense_variant	Exon 8 of 9		XP_047286921.1
ZFYVE26	XM_047431173.1	c.*548G>T		3_prime_UTR_variant	Exon 42 of 42		XP_047287129.1
GPHN	XM_047430879.1	c.1313-6001C>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.662C>A	p.Thr221Asn	missense_variant	Exon 8 of 9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.662C>A	p.Thr221Asn	missense_variant	Exon 7 of 8	5		ENSP00000267502.3
RDH12	ENST00000552873.1	n.31C>A		non_coding_transcript_exon_variant	Exon 2 of 2	5
ZFYVE26	ENST00000394455.6	n.3288+17G>T		intron_variant	Intron 14 of 14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.86	P;P
Vest4		0.67
MutPred		0.34		Loss of catalytic residue at T221 (P = 0.1428);Loss of catalytic residue at T221 (P = 0.1428);
MVP		0.96
MPC		0.26
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs769317754; hg19: chr14-68195911;