1-68439684-ATT-ATTT

Position:

• chr1-68439684-ATT-ATTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000329.3(RPE65):​c.644-43_644-42insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,259,218 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (1 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.145

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00252 (377/149640) while in subpopulation AFR AF= 0.00739 (302/40844). AF 95% confidence interval is 0.00671. There are 2 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPE65	NM_000329.3	c.644-43_644-42insA		intron_variant		ENST00000262340.6
LOC124904198	XR_007066164.1	n.72-8838dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPE65	ENST00000262340.6	c.644-43_644-42insA		intron_variant		1	NM_000329.3	P1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 378 AN: 149542 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00742

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00214

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000550

Gnomad OTH AF: 0.000981

GnomAD4 exome AF: 0.00684 AC: 7584 AN: 1109578 Hom.: 1 Cov.: 18 AF XY: 0.00633 AC XY: 3526 AN XY: 557180

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00953

Gnomad4 SAS exome AF: 0.00287

Gnomad4 FIN exome AF: 0.00347

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00695

GnomAD4 genome AF: 0.00252 AC: 377 AN: 149640 Hom.: 2 Cov.: 32 AF XY: 0.00220 AC XY: 161 AN XY: 73036

Gnomad4 AFR AF: 0.00739

Gnomad4 AMR AF: 0.00140

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00215

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000395

Gnomad4 NFE AF: 0.000550

Gnomad4 OTH AF: 0.000972

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs61752894; hg19: chr1-68905367;