1-68439684-ATT-ATTT

Variant names:

• chr1-68439684-A-AT
• rs61752894
• NM_000329.3:c.644-43dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000329.3(RPE65):​c.644-43dupA 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
• Publications: 0 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):

• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Leber congenital amaurosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• RPE65-related recessive retinopathy

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

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3	c.644-43dupA		intron_variant	Intron 6 of 13	ENST00000262340.6	NP_000320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPE65	ENST00000262340.6	c.644-43_644-42insA		intron_variant	Intron 6 of 13	1	NM_000329.3	ENSP00000262340.5

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

GnomAD2 exomes AF: 0.00230 AC: 413 AN: 179820 AF XY: 0.00209

Gnomad AFR exome AF: 0.00830

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000586

Gnomad EAS exome AF: 0.00300

Gnomad FIN exome AF: 0.00418

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.00164

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0118 AC: 288 AN: 24446

American (AMR) AF: 0.00230 AC: 80 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 57 AN: 20446

East Asian (EAS) AF: 0.00953 AC: 284 AN: 29804

South Asian (SAS) AF: 0.00287 AC: 199 AN: 69376

European-Finnish (FIN) AF: 0.00347 AC: 146 AN: 42076

Middle Eastern (MID) AF: 0.00322 AC: 15 AN: 4656

European-Non Finnish (NFE) AF: 0.00739 AC: 6199 AN: 838496

Other (OTH) AF: 0.00695 AC: 316 AN: 45490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00739 AC: 302 AN: 40844

American (AMR) AF: 0.00140 AC: 21 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.00215 AC: 11 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.000395 AC: 4 AN: 10126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000550 AC: 37 AN: 67212

Other (OTH) AF: 0.000972 AC: 2 AN: 2058

Alfa AF: 0.000433 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61752894; hg19: chr1-68905367;