14-67722520-C-T

Variant names:

• chr14-67722520-C-T
• rs960563752
• NM_152443.3:c.-123C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152443.3(RDH12):​c.-123C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000665 in 827,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: RDH12 NM_152443.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.425
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152443.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	NM_152443.3	MANE Select	c.-123C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_689656.2	A0A0S2Z613
	RDH12	NM_152443.3	MANE Select	c.-123C>T		5_prime_UTR	Exon 3 of 9	NP_689656.2	A0A0S2Z613

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	ENST00000551171.6	TSL:1 MANE Select	c.-123C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000449079.1	Q96NR8
	RDH12	ENST00000551171.6	TSL:1 MANE Select	c.-123C>T		5_prime_UTR	Exon 3 of 9	ENSP00000449079.1	Q96NR8
	RDH12	ENST00000267502.3	TSL:5	c.-123C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000267502.3	Q96NR8

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.0000622 AC: 42 AN: 675050 Hom.: 0 Cov.: 8 AF XY: 0.0000740 AC XY: 27 AN XY: 365040

African (AFR) AF: 0.00 AC: 0 AN: 18520

American (AMR) AF: 0.000573 AC: 25 AN: 43656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21184

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36138

South Asian (SAS) AF: 0.0000285 AC: 2 AN: 70288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.0000329 AC: 13 AN: 395352

Other (OTH) AF: 0.0000290 AC: 1 AN: 34528

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.000523 AC: 8 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00144 AC: 3 AN: 2084

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.2
DANN	Benign	0.68
PhyloP100		0.42

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: rs960563752; hg19: chr14-68189237;