NM_152443.3:c.-275+2688T>C

Variant names:

• chr14-67704623-T-C
• rs12147616
• NM_152443.3:c.-275+2688T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152443.3(RDH12):​c.-275+2688T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,152 control chromosomes in the GnomAD database, including 1,473 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1473 hom., cov: 32)
• Consequence: RDH12 NM_152443.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 1 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3	c.-275+2688T>C		intron_variant	Intron 1 of 8	ENST00000551171.6	NP_689656.2
GPHN	XM_047430879.1	c.1313-30572T>C		intron_variant	Intron 14 of 14		XP_047286835.1
RDH12	XM_047430965.1	c.-309+2688T>C		intron_variant	Intron 1 of 8		XP_047286921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.-275+2688T>C		intron_variant	Intron 1 of 8	1	NM_152443.3	ENSP00000449079.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19208 AN: 152034 Hom.: 1477 Cov.: 32

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.126 AC: 19206 AN: 152152 Hom.: 1473 Cov.: 32 AF XY: 0.134 AC XY: 9948 AN XY: 74372

African (AFR) AF: 0.0830 AC: 3445 AN: 41520

American (AMR) AF: 0.156 AC: 2393 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 449 AN: 3464

East Asian (EAS) AF: 0.237 AC: 1224 AN: 5160

South Asian (SAS) AF: 0.335 AC: 1618 AN: 4824

European-Finnish (FIN) AF: 0.135 AC: 1424 AN: 10582

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8193 AN: 67990

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.126 Hom.: 502

Bravo AF: 0.123

Asia WGS AF: 0.269 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.65
DANN	Benign	0.46
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12147616; hg19: chr14-68171340;