1-68431559-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000329.3(RPE65):c.1155G>A(p.Thr385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,808 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• 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:9 O:1
• Conservation: PhyloP100: -1.47

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]

LOC124904198 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-68431559-C-T is Benign according to our data. Variant chr1-68431559-C-T is described in ClinVar as [Benign]. Clinvar id is 98828.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-68431559-C-T is described in Lovd as [Benign]. Variant chr1-68431559-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00562 (855/152222) while in subpopulation AFR AF= 0.017 (705/41530). AF 95% confidence interval is 0.0159. There are 4 homozygotes in gnomad4. There are 423 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.1155G>A	p.Thr385=	synonymous_variant	11/14	ENST00000262340.6
LOC124904198	XR_007066164.1	n.71+11438C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.1155G>A	p.Thr385=	synonymous_variant	11/14	1	NM_000329.3	P1

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

GnomAD3 exomes AF: 0.00200 AC: 502 AN: 250418 Hom.: 1 AF XY: 0.00182 AC XY: 246 AN XY: 135288

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 SAS exome AF: 0.000621

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

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000490

Gnomad4 OTH exome AF: 0.00252

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

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00650

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

RPE65-related recessive retinopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Dec 22, 2023

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). -

Leber congenital amaurosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 15, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20;C5231465:Retinitis pigmentosa 87 with choroidal involvement Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 15, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.079
Dann	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs62653014; hg19: chr1-68897242;