chr1-68429245-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000329.3(RPE65):c.*531A>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 0.183 in 154,528 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2659 hom., cov: 32)

Exomes 𝑓: 0.20 ( 53 hom. )

Consequence

RPE65
NM_000329.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.735

Publications

2 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
RPE65-related recessive retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
retinitis pigmentosa 20
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
RPE65-related dominant retinopathy
Inheritance: AD Classification: STRONG Submitted by: ClinGen
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

RPE65 links:

LOC124904198 (HGNC:):

LOC124904198 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-68429245-T-C is Benign according to our data. Variant chr1-68429245-T-C is described in ClinVar as Benign. ClinVar VariationId is 298015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.227 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPE65	NM_000329.3	MANE Select	c.*531A>G	3_prime_UTR	Exon 14 of 14	NP_000320.1	Q16518
RPE65	NM_001406853.1		c.*531A>G	3_prime_UTR	Exon 13 of 13	NP_001393782.1
RPE65	NM_001406856.1		c.*531A>G	3_prime_UTR	Exon 13 of 13	NP_001393785.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPE65	ENST00000262340.6	TSL:1 MANE Select	c.*531A>G	3_prime_UTR	Exon 14 of 14	ENSP00000262340.5	Q16518
RPE65	ENST00000713936.1		n.*2038A>G	non_coding_transcript_exon	Exon 15 of 15	ENSP00000519233.1	A0AAQ5BH58
RPE65	ENST00000713937.1		n.*1281A>G	non_coding_transcript_exon	Exon 13 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27688

AN:

151962

Hom.:

2649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0495

Gnomad AMR

AF:

0.233

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.174

GnomAD4 exome

AF:

0.200

AC:

490

AN:

2448

Hom.:

Cov.:

AF XY:

0.202

AC XY:

278

AN XY:

1376

show subpopulations

African (AFR)

AF:

0.200

AC:

AN:

American (AMR)

AF:

0.318

AC:

114

AN:

358

Ashkenazi Jewish (ASJ)

AF:

0.0714

AC:

AN:

East Asian (EAS)

AF:

0.204

AC:

AN:

South Asian (SAS)

AF:

0.271

AC:

AN:

166

European-Finnish (FIN)

AF:

0.273

AC:

AN:

Middle Eastern (MID)

AF:

0.250

AC:

AN:

European-Non Finnish (NFE)

AF:

0.171

AC:

295

AN:

1724

Other (OTH)

AF:

0.156

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.182

AC:

27726

AN:

152080

Hom.:

2659

Cov.:

AF XY:

0.185

AC XY:

13716

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.202

AC:

8389

AN:

41488

American (AMR)

AF:

0.233

AC:

3566

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

463

AN:

3468

East Asian (EAS)

AF:

0.141

AC:

726

AN:

5164

South Asian (SAS)

AF:

0.218

AC:

1052

AN:

4820

European-Finnish (FIN)

AF:

0.222

AC:

2353

AN:

10576

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.158

AC:

10745

AN:

67970

Other (OTH)

AF:

0.171

AC:

361

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1162

2324

3487

4649

5811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

852

Bravo

AF:

0.186

Asia WGS

AF:

0.159

AC:

551

AN:

3472

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 2 (1)

not provided (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.1

(source)

DANN

Benign

0.68

PhyloP100

0.73

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over