dbSNP rs2182315: RPE65:c.*611G>A (chr1-68429165-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000329.3(RPE65):c.*611G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,336 control chromosomes in the GnomAD database, including 15,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15193 hom., cov: 33)

Exomes 𝑓: 0.28 ( 13 hom. )

Consequence

RPE65
NM_000329.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.392

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-68429165-C-T is Benign according to our data. Variant chr1-68429165-C-T is described in ClinVar as [Benign]. Clinvar id is 298013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3 link	c.*611G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000262340.6	NP_000320.1	Q16518

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340 link	c.*611G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000329.3	ENSP00000262340.5		Q16518

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

65022

AN:

151862

Hom.:

15169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.567

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.419

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.769

Gnomad SAS

AF:

0.580

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.402

GnomAD4 exome

AF:

0.280

AC:

AN:

354

Hom.:

Cov.:

AF XY:

0.322

AC XY:

AN XY:

208

show subpopulations

Gnomad4 AMR exome

AF:

0.458

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.428

AC:

65088

AN:

151982

Hom.:

15193

Cov.:

AF XY:

0.435

AC XY:

32326

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.566

Gnomad4 AMR

AF:

0.419

Gnomad4 ASJ

AF:

0.266

Gnomad4 EAS

AF:

0.769

Gnomad4 SAS

AF:

0.579

Gnomad4 FIN

AF:

0.371

Gnomad4 NFE

AF:

0.330

Gnomad4 OTH

AF:

0.404

Alfa

AF:

0.368

Hom.:

4167

Bravo

AF:

0.435

Asia WGS

AF:

0.611

AC:

2103

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leber congenital amaurosis 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.41

DANN

Benign

0.35

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