rs12145904

Variant names:

• chr1-68438259-C-T
• rs12145904
• NM_000329.3:c.1056G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-68438259-C-T
• chr1-68438259-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000329.3:c.1056G>A variant is a synonymous variant in codon 352 of RPE65, and is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.3944, with 8033 alleles / 19884 total alleles in the East Asian population with 1627 homozygotes, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The variant does not have a strong prediction of impact at splicing sites according to SpliceAI, which calculates a delta score of 0.12 for splice acceptor gain. Because this score is higher than the ClinGen LCA / eoRD VCEP BP4 / BP7 threshold of <0.1 and lower than the PP3 threshold of >0.2, no in silico predictive codes are met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA285811/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.16 (2342 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14595 hom.)
• Consequence: RPE65 NM_000329.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: 0.00100
• Publications: 23 publications found

Genes affected

RPE65 (HGNC:10294): (retinoid isomerohydrolase RPE65) The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]

RPE65 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• RPE65-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• RPE65-related dominant retinopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
• retinitis pigmentosa 20

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 87 with choroidal involvement

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC124904198 (HGNC:):

ACMG classification

Specifications for RPE65 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000329.3. 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
	RPE65	NM_000329.3	MANE Select	c.1056G>A	p.Glu352Glu	synonymous	Exon 10 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.948G>A	p.Glu316Glu	synonymous	Exon 9 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.780G>A	p.Glu260Glu	synonymous	Exon 9 of 13	NP_001393785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.1056G>A	p.Glu352Glu	synonymous	Exon 10 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*961G>A		non_coding_transcript_exon	Exon 11 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.1056G>A		non_coding_transcript_exon	Exon 10 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24502 AN: 151892 Hom.: 2339 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0900

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.154 AC: 38661 AN: 251046 AF XY: 0.153

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0908

Gnomad EAS exome AF: 0.402

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.132 AC: 192190 AN: 1461228 Hom.: 14595 Cov.: 32 AF XY: 0.132 AC XY: 96194 AN XY: 726940

African (AFR) AF: 0.228 AC: 7642 AN: 33462

American (AMR) AF: 0.121 AC: 5415 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0906 AC: 2366 AN: 26122

East Asian (EAS) AF: 0.372 AC: 14741 AN: 39672

South Asian (SAS) AF: 0.185 AC: 15916 AN: 86232

European-Finnish (FIN) AF: 0.0996 AC: 5313 AN: 53342

Middle Eastern (MID) AF: 0.111 AC: 642 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 131727 AN: 1111574

Other (OTH) AF: 0.140 AC: 8428 AN: 60368

GnomAD4 genome AF: 0.161 AC: 24519 AN: 152010 Hom.: 2342 Cov.: 32 AF XY: 0.164 AC XY: 12171 AN XY: 74320

African (AFR) AF: 0.227 AC: 9387 AN: 41430

American (AMR) AF: 0.147 AC: 2253 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 312 AN: 3466

East Asian (EAS) AF: 0.389 AC: 1998 AN: 5140

South Asian (SAS) AF: 0.193 AC: 931 AN: 4818

European-Finnish (FIN) AF: 0.100 AC: 1058 AN: 10578

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8033 AN: 67980

Other (OTH) AF: 0.155 AC: 328 AN: 2114

Alfa AF: 0.132 Hom.: 1173

Bravo AF: 0.167

Asia WGS AF: 0.232 AC: 805 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.117

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Leber congenital amaurosis 2 (2)
-	-	2	not specified (2)
-	-	1	Leber congenital amaurosis (1)
-	-	1	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (1)
-	-	1	not provided (2)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 87 with choroidal involvement (1)
-	-	1	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.6
DANN	Benign	0.47
PhyloP100		0.0010
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12145904; hg19: chr1-68903942; COSMIC: COSV52016397;