rs61752893

chr1-68439683-TA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_000329.3(RPE65):c.644-42del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,522,372 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Likely benign reviewed by expert panel B:2 O:1
• Conservation: PhyloP100: -2.55

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-68439683-TA-T is Benign according to our data. Variant chr1-68439683-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 98885.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-68439683-TA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000247 (338/1370198) while in subpopulation MID AF= 0.0106 (59/5584). AF 95% confidence interval is 0.00841. There are 0 homozygotes in gnomad4_exome. There are 155 alleles in male gnomad4_exome subpopulation. Median coverage is 20. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.644-42del		intron_variant		ENST00000262340.6
LOC124904198	XR_007066164.1	n.72-8848del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.644-42del		intron_variant		1	NM_000329.3	P1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000317 AC: 79 AN: 249042 Hom.: 0 AF XY: 0.000237 AC XY: 32 AN XY: 134804

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000247 AC: 338 AN: 1370198 Hom.: 0 Cov.: 20 AF XY: 0.000226 AC XY: 155 AN XY: 687092

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.000697

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000279

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74418

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RPE65-related recessive retinopathy Benign:1

Likely benign, reviewed by expert panel

curation

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

Apr 22, 2024

The c.644-42del variant in RPE65, is an intronic variant which is present outside of consensus splice sites. The splicing impact predictor SpliceAI gives a delta score of 0.09, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In addition, the PhyloP score was -2.63 which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1, which depicts that the nucleotide is not highly conserved. This intronic variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.000827, with 26/24712 in the African/ African-American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). In summary this variant meets criteria to be classified as Likely Benign for Leber congenital amaurosis (RPE65) based on the ACMG/AMP criteria (codes met: BP4, BP7, BS1). (VCEP specifications version 1.0.0; date of approval 09/21/2023). -

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Nov 20, 2017

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs61752893; hg19: chr1-68905366;