1-68429245-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000329.3(RPE65):c.*531A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 154,528 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.18 ( 2659 hom., cov: 32)

Exomes 𝑓: 0.20 ( 53 hom. )

Consequence

RPE65
NM_000329.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.735

Variant links:

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 links:

LOC124904198 (HGNC:):

LOC124904198 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-68429245-T-C is Benign according to our data. Variant chr1-68429245-T-C is described in ClinVar as [Benign]. Clinvar id is 298015.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3 linkuse as main transcript	c.*531A>G		3_prime_UTR_variant	14/14	ENST00000262340.6
LOC124904198	XR_007066164.1 linkuse as main transcript	n.71+9124T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6 linkuse as main transcript	c.*531A>G		3_prime_UTR_variant	14/14	1	NM_000329.3	P1

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27688

AN:

151962

Hom.:

2649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0495

Gnomad AMR

AF:

0.233

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.174

GnomAD4 exome

AF:

0.200

AC:

490

AN:

2448

Hom.:

Cov.:

AF XY:

0.202

AC XY:

278

AN XY:

1376

show subpopulations

Gnomad4 AFR exome

AF:

0.200

Gnomad4 AMR exome

AF:

0.318

Gnomad4 ASJ exome

AF:

0.0714

Gnomad4 EAS exome

AF:

0.204

Gnomad4 SAS exome

AF:

0.271

Gnomad4 FIN exome

AF:

0.273

Gnomad4 NFE exome

AF:

0.171

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.182

AC:

27726

AN:

152080

Hom.:

2659

Cov.:

AF XY:

0.185

AC XY:

13716

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.202

Gnomad4 AMR

AF:

0.233

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.141

Gnomad4 SAS

AF:

0.218

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.158

Gnomad4 OTH

AF:

0.171

Alfa

AF:

0.170

Hom.:

473

Bravo

AF:

0.186

Asia WGS

AF:

0.159

AC:

551

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leber congenital amaurosis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

6.1

Dann

Benign

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over