rs910315

Variant names:

• chr14-67722206-A-G
• rs910315
• NM_152443.3:c.-219-218A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_152443.3(RDH12):​c.-219-218A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 152,108 control chromosomes in the GnomAD database, including 853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.089 (853 hom., cov: 32)
• Consequence: RDH12 NM_152443.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.239
• Publications: 2 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, ClinGen, 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-67722206-A-G is Benign according to our data. Variant chr14-67722206-A-G is described in ClinVar as Benign. ClinVar VariationId is 1231282.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

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.-219-218A>G		intron	N/A	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.-219-218A>G		intron	N/A	ENSP00000449079.1	Q96NR8
	RDH12	ENST00000267502.3	TSL:5	c.-219-218A>G		intron	N/A	ENSP00000267502.3	Q96NR8

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 13494 AN: 151990 Hom.: 851 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0845

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

GnomAD4 genome AF: 0.0890 AC: 13537 AN: 152108 Hom.: 853 Cov.: 32 AF XY: 0.0890 AC XY: 6618 AN XY: 74362

African (AFR) AF: 0.148 AC: 6155 AN: 41472

American (AMR) AF: 0.144 AC: 2190 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3468

East Asian (EAS) AF: 0.232 AC: 1198 AN: 5160

South Asian (SAS) AF: 0.0967 AC: 466 AN: 4820

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0425 AC: 2893 AN: 68006

Other (OTH) AF: 0.0860 AC: 182 AN: 2116

Alfa AF: 0.0591 Hom.: 234

Bravo AF: 0.104

Asia WGS AF: 0.163 AC: 564 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.91
DANN	Benign	0.62
PhyloP100		-0.24
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: rs910315; hg19: chr14-68188923;