1-68439684-ATT-AT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000329.3(RPE65):​c.644-43delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,227,498 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.012 (6 hom.)
• Consequence: RPE65 NM_000329.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1 O:1
• 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 -9 ACMG points.

• BP6: Variant 1-68439684-AT-A is Benign according to our data. Variant chr1-68439684-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 98886.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00219 (327/149588) while in subpopulation AMR AF = 0.00428 (64/14964). AF 95% confidence interval is 0.00344. There are 0 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPE65	NM_000329.3	c.644-43delA		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.644-43delA		intron_variant	Intron 6 of 13	1	NM_000329.3	ENSP00000262340.5

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 326 AN: 149492 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00428

Gnomad ASJ AF: 0.000584

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00245

GnomAD2 exomes AF: 0.00799 AC: 1436 AN: 179820 AF XY: 0.00863

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00812

Gnomad ASJ exome AF: 0.00410

Gnomad EAS exome AF: 0.00450

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00869

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.0125 AC: 13459 AN: 1077910 Hom.: 6 Cov.: 18 AF XY: 0.0119 AC XY: 6418 AN XY: 540352

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

African (AFR) AF: 0.00940 AC: 220 AN: 23416

American (AMR) AF: 0.00809 AC: 264 AN: 32636

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 130 AN: 19532

East Asian (EAS) AF: 0.00525 AC: 148 AN: 28184

South Asian (SAS) AF: 0.00700 AC: 460 AN: 65712

European-Finnish (FIN) AF: 0.00699 AC: 283 AN: 40486

Middle Eastern (MID) AF: 0.00707 AC: 32 AN: 4528

European-Non Finnish (NFE) AF: 0.0139 AC: 11428 AN: 819316

Other (OTH) AF: 0.0112 AC: 494 AN: 44100

⚠️ 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: 0.00219 AC: 327 AN: 149588 Hom.: 0 Cov.: 32 AF XY: 0.00229 AC XY: 167 AN XY: 73004

African (AFR) AF: 0.000441 AC: 18 AN: 40844

American (AMR) AF: 0.00428 AC: 64 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.000584 AC: 2 AN: 3426

East Asian (EAS) AF: 0.000780 AC: 4 AN: 5126

South Asian (SAS) AF: 0.000214 AC: 1 AN: 4682

European-Finnish (FIN) AF: 0.00139 AC: 14 AN: 10106

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

European-Non Finnish (NFE) AF: 0.00326 AC: 219 AN: 67192

Other (OTH) AF: 0.00243 AC: 5 AN: 2058

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00208

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:1

Mar 27, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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)		0.020		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; COSMIC: COSV52013806;