chr1-68429047-G-GCT

Variant names:

• chr1-68429047-G-GCT
• rs10626313
• NM_000329.3:c.*727_*728dupAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000329.3(RPE65):​c.*727_*728dupAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene RPE65 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.43 (15091 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: RPE65 NM_000329.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• RPE65-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• RPE65-related dominant retinopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
• retinitis pigmentosa 20

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 87 with choroidal involvement

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC124904198 (HGNC:):

ACMG classification

Specifications for RPE65 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	NM_000329.3	MANE Select	c.*727_*728dupAG		3_prime_UTR	Exon 14 of 14	NP_000320.1	Q16518
	RPE65	NM_001406853.1		c.*727_*728dupAG		3_prime_UTR	Exon 13 of 13	NP_001393782.1
	RPE65	NM_001406856.1		c.*727_*728dupAG		3_prime_UTR	Exon 13 of 13	NP_001393785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPE65	ENST00000262340.6	TSL:1 MANE Select	c.*727_*728dupAG		3_prime_UTR	Exon 14 of 14	ENSP00000262340.5	Q16518
	RPE65	ENST00000713936.1		n.*2234_*2235dupAG		non_coding_transcript_exon	Exon 15 of 15	ENSP00000519233.1	A0AAQ5BH58
	RPE65	ENST00000713937.1		n.*1477_*1478dupAG		non_coding_transcript_exon	Exon 13 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64789 AN: 151536 Hom.: 15069 Cov.: 0

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.260

Gnomad NFE AF: 0.329

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.428 AC: 64852 AN: 151654 Hom.: 15091 Cov.: 0 AF XY: 0.435 AC XY: 32214 AN XY: 74106

African (AFR) AF: 0.566 AC: 23396 AN: 41348

American (AMR) AF: 0.419 AC: 6385 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 924 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3965 AN: 5164

South Asian (SAS) AF: 0.578 AC: 2787 AN: 4820

European-Finnish (FIN) AF: 0.370 AC: 3893 AN: 10512

Middle Eastern (MID) AF: 0.262 AC: 75 AN: 286

European-Non Finnish (NFE) AF: 0.329 AC: 22333 AN: 67794

Other (OTH) AF: 0.404 AC: 850 AN: 2104

Alfa AF: 0.376 Hom.: 1220

Asia WGS AF: 0.609 AC: 2084 AN: 3430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10626313; hg19: chr1-68894730; COSMIC: COSV52012835;