1-68439675-G-C

Position:

• chr1-68439675-G-C

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.644-33C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,560,052 control chromosomes in the GnomAD database, including 172,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (25054 hom., cov: 31)
  • Exomes 𝑓: 0.44 (147305 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.52

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=-0.88).
• BP6: Variant 1-68439675-G-C is Benign according to our data. Variant chr1-68439675-G-C is described in ClinVar as [Benign]. Clinvar id is 255839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-68439675-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPE65	NM_000329.3	c.644-33C>G		intron_variant		ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.644-33C>G		intron_variant		1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82358 AN: 151784 Hom.: 25003 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.881

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.506

GnomAD3 exomes AF: 0.527 AC: 131900 AN: 250364 Hom.: 38854 AF XY: 0.514 AC XY: 69604 AN XY: 135294

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.882

Gnomad SAS exome AF: 0.600

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.452

GnomAD4 exome AF: 0.440 AC: 619414 AN: 1408150 Hom.: 147305 Cov.: 24 AF XY: 0.442 AC XY: 311186 AN XY: 703690

Gnomad4 AFR exome AF: 0.788

Gnomad4 AMR exome AF: 0.702

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.892

Gnomad4 SAS exome AF: 0.599

Gnomad4 FIN exome AF: 0.420

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.543 AC: 82474 AN: 151902 Hom.: 25054 Cov.: 31 AF XY: 0.549 AC XY: 40730 AN XY: 74250

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.881

Gnomad4 SAS AF: 0.608

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.506

Alfa AF: 0.328 Hom.: 1322

Bravo AF: 0.566

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Leber congenital amaurosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinitis pigmentosa 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.39
DANN	Benign	0.56

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: rs1925955; hg19: chr1-68905358; COSMIC: COSV52014531;