1-68439683-TA-T

Variant names:

• chr1-68439683-TA-T
• rs61752893
• NM_000329.3:c.644-42delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1 BP7 BP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226572/MONDO:0100368/120

• 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
• Publications: 1 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):

• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• RPE65-related recessive retinopathy

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

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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: Likely_benign. The variant received -6 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.
• BS1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	NM_000329.3	MANE Select	c.644-42delT		intron	N/A	NP_000320.1
	RPE65	NM_001406853.1		c.536-42delT		intron	N/A	NP_001393782.1
	RPE65	NM_001406856.1		c.368-42delT		intron	N/A	NP_001393785.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.644-42delT		intron	N/A	ENSP00000262340.5
	RPE65	ENST00000713936.1		n.*549-42delT		intron	N/A	ENSP00000519233.1
	RPE65	ENST00000713937.1		n.644-42delT		intron	N/A	ENSP00000519234.1

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

GnomAD2 exomes AF: 0.000317 AC: 79 AN: 249042 AF XY: 0.000237

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00125 AC: 39 AN: 31318

American (AMR) AF: 0.000697 AC: 31 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25580

East Asian (EAS) AF: 0.00 AC: 0 AN: 39180

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.0106 AC: 59 AN: 5584

European-Non Finnish (NFE) AF: 0.000187 AC: 192 AN: 1029402

Other (OTH) AF: 0.000279 AC: 16 AN: 57250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000747 AC: 31 AN: 41506

American (AMR) AF: 0.000524 AC: 8 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000453

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 (1)
-	-	1	RPE65-related recessive retinopathy (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

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: rs61752893; hg19: chr1-68905366;