1-68428861-G-C

Position:

• chr1-68428861-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.*915C>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 0.428 in 151,762 control chromosomes in the GnomAD database, including 15,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15178 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: RPE65 NM_000329.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.457

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=-0.99).
• BP6: Variant 1-68428861-G-C is Benign according to our data. Variant chr1-68428861-G-C is described in ClinVar as [Benign]. Clinvar id is 298010.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/exons	MANE	Protein	UniProt
RPE65	NM_000329.3	c.*915C>G		3_prime_UTR_variant	14/14	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340	c.*915C>G		3_prime_UTR_variant	14/14	1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64952 AN: 151642 Hom.: 15154 Cov.: 33

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.402

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.428 AC: 65018 AN: 151762 Hom.: 15178 Cov.: 33 AF XY: 0.435 AC XY: 32279 AN XY: 74136

Gnomad4 AFR AF: 0.567

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.267

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: 0.205 Hom.: 409

Bravo AF: 0.435

Asia WGS AF: 0.611 AC: 2098 AN: 3442

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Leber congenital amaurosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.27
DANN	Benign	0.38

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: rs3118416; hg19: chr1-68894544; COSMIC: COSV52014346;