rs577675068

Variant names:

• chr1-68429040-AT-A
• rs577675068
• NM_000329.3:c.*735delA

Your query was ambiguous. Multiple possible variants found:

• chr1-68429040-AT-A
• chr1-68429040-AT-ATT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_000329.3(RPE65):​c.*735delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 120,490 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00012 (1 hom., cov: 32)
• Consequence: RPE65 NM_000329.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0810
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• RPE65-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• retinitis pigmentosa 20

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• RPE65-related dominant retinopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000116 (14/120490) while in subpopulation EAS AF = 0.00665 (14/2104). AF 95% confidence interval is 0.00402. There are 1 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*735delA		3_prime_UTR	Exon 14 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.*735delA		3_prime_UTR	Exon 13 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.*735delA		3_prime_UTR	Exon 13 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.*735delA		3_prime_UTR	Exon 14 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*2242delA		non_coding_transcript_exon	Exon 15 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.*1485delA		non_coding_transcript_exon	Exon 13 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 14 AN: 120418 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00664

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.000116 AC: 14 AN: 120490 Hom.: 1 Cov.: 32 AF XY: 0.000137 AC XY: 8 AN XY: 58332

African (AFR) AF: 0.00 AC: 0 AN: 27550

American (AMR) AF: 0.00 AC: 0 AN: 12428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3262

East Asian (EAS) AF: 0.00665 AC: 14 AN: 2104

South Asian (SAS) AF: 0.00 AC: 0 AN: 3116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60234

Other (OTH) AF: 0.00 AC: 0 AN: 1694

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis (1)
-	1	-	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.081
Mutation Taster		=100/0	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: rs577675068; hg19: chr1-68894723;