1-68431262-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000329.3(RPE65):c.1338+20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,611,388 control chromosomes in the GnomAD database, including 4,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (517 hom., cov: 32)
  • Exomes 𝑓: 0.036 (3939 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.507

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-68431262-T-G is Benign according to our data. Variant chr1-68431262-T-G is described in ClinVar as [Benign]. Clinvar id is 98841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-68431262-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.1338+20A>C		intron_variant		ENST00000262340.6
LOC124904198	XR_007066164.1	n.71+11141T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.1338+20A>C		intron_variant		1	NM_000329.3	P1

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5667 AN: 152110 Hom.: 519 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0665 AC: 16646 AN: 250472 Hom.: 1832 AF XY: 0.0666 AC XY: 9020 AN XY: 135368

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.0584

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.403

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0562

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0404

GnomAD4 exome AF: 0.0363 AC: 52941 AN: 1459160 Hom.: 3939 Cov.: 31 AF XY: 0.0381 AC XY: 27666 AN XY: 726086

Gnomad4 AFR exome AF: 0.00395

Gnomad4 AMR exome AF: 0.0584

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.371

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0436

GnomAD4 genome AF: 0.0372 AC: 5665 AN: 152228 Hom.: 517 Cov.: 32 AF XY: 0.0436 AC XY: 3245 AN XY: 74410

Gnomad4 AFR AF: 0.00669

Gnomad4 AMR AF: 0.0555

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0562

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0204 Hom.: 105

Bravo AF: 0.0363

Asia WGS AF: 0.189 AC: 654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -

Retinitis pigmentosa 87 with choroidal involvement Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Leber congenital amaurosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12564647; hg19: chr1-68896945; COSMIC: COSV52013097;