rs62653014

Variant names:

• chr1-68431559-C-T
• rs62653014
• NM_000329.3:c.1155G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-68431559-C-T
• chr1-68431559-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: NM_000329.3(RPE65):c.1155G>A (p.Thr385=) is a synonymous variant at codon 385. The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01596, with 704 alleles / 41408 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). 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, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226488/MONDO:0100368/120

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: RPE65 NM_000329.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10 O:1
• Conservation: PhyloP100: -1.47
• Publications: 2 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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1155G>A	p.Thr385Thr	synonymous	Exon 11 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.1047G>A	p.Thr349Thr	synonymous	Exon 10 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.879G>A	p.Thr293Thr	synonymous	Exon 10 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.1155G>A	p.Thr385Thr	synonymous	Exon 11 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*1060G>A		non_coding_transcript_exon	Exon 12 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.*209G>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152104 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00200 AC: 502 AN: 250418 AF XY: 0.00182

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00111 AC: 1621 AN: 1461586 Hom.: 8 Cov.: 32 AF XY: 0.00107 AC XY: 775 AN XY: 727084

African (AFR) AF: 0.0191 AC: 638 AN: 33460

American (AMR) AF: 0.00255 AC: 114 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39692

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53398

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000490 AC: 545 AN: 1111830

Other (OTH) AF: 0.00252 AC: 152 AN: 60384

GnomAD4 genome AF: 0.00562 AC: 855 AN: 152222 Hom.: 4 Cov.: 32 AF XY: 0.00568 AC XY: 423 AN XY: 74414

African (AFR) AF: 0.0170 AC: 705 AN: 41530

American (AMR) AF: 0.00556 AC: 85 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00231 Hom.: 1

Bravo AF: 0.00650

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (2)
-	-	1	Leber congenital amaurosis 2 (1)
-	-	1	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	RPE65-related recessive retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.079
DANN	Benign	0.45
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism

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: rs62653014; hg19: chr1-68897242;