rs2274321

Positions:

• chr1-68440831-G-A

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.643+22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,358 control chromosomes in the GnomAD database, including 1,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (137 hom., cov: 32)
  • Exomes 𝑓: 0.025 (1031 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.352

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=-0.59).
• BP6: Variant 1-68440831-G-A is Benign according to our data. Variant chr1-68440831-G-A is described in ClinVar as [Benign]. Clinvar id is 255838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.643+22C>T		intron_variant		ENST00000262340.6
LOC124904198	XR_007066164.1	n.72-7701G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.643+22C>T		intron_variant		1	NM_000329.3	P1

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4931 AN: 152126 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0324 AC: 8127 AN: 250972 Hom.: 298 AF XY: 0.0364 AC XY: 4939 AN XY: 135672

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.0100

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0253 AC: 37001 AN: 1461114 Hom.: 1031 Cov.: 31 AF XY: 0.0282 AC XY: 20491 AN XY: 726894

Gnomad4 AFR exome AF: 0.0637

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0408

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0325 AC: 4941 AN: 152244 Hom.: 137 Cov.: 32 AF XY: 0.0336 AC XY: 2497 AN XY: 74426

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.0247

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0157

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0271 Hom.: 21

Bravo AF: 0.0322

Asia WGS AF: 0.0580 AC: 200 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Retinitis pigmentosa 87 with choroidal involvement Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Leber congenital amaurosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.4
DANN	Benign	0.79

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: rs2274321; hg19: chr1-68906514;