chr1-68439675-G-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.644-33C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,560,052 control chromosomes in the GnomAD database, including 172,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 25054 hom., cov: 31)

Exomes 𝑓: 0.44 ( 147305 hom. )

Consequence

RPE65
NM_000329.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.52

Publications

6 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: 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

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=-0.88).

BP6

Variant 1-68439675-G-C is Benign according to our data. Variant chr1-68439675-G-C is described in ClinVar as Benign. ClinVar VariationId is 255839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 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.644-33C>G	intron	N/A	NP_000320.1	Q16518
RPE65	NM_001406853.1		c.536-33C>G	intron	N/A	NP_001393782.1
RPE65	NM_001406856.1		c.368-33C>G	intron	N/A	NP_001393785.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RPE65	ENST00000262340.6	TSL:1 MANE Select	c.644-33C>G	intron	N/A	ENSP00000262340.5	Q16518
RPE65	ENST00000713936.1		n.*549-33C>G	intron	N/A	ENSP00000519233.1	A0AAQ5BH58
RPE65	ENST00000713937.1		n.644-33C>G	intron	N/A	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes

AF:

0.543

AC:

82358

AN:

151784

Hom.:

25003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.783

Gnomad AMI

AF:

0.293

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.881

Gnomad SAS

AF:

0.609

Gnomad FIN

AF:

0.417

Gnomad MID

AF:

0.293

Gnomad NFE

AF:

0.393

Gnomad OTH

AF:

0.506

GnomAD2 exomes

AF:

0.527

AC:

131900

AN:

250364

AF XY:

0.514

show subpopulations

Gnomad AFR exome

AF:

0.794

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.882

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.452

GnomAD4 exome

AF:

0.440

AC:

619414

AN:

1408150

Hom.:

147305

Cov.:

AF XY:

0.442

AC XY:

311186

AN XY:

703690

show subpopulations

African (AFR)

AF:

0.788

AC:

25595

AN:

32472

American (AMR)

AF:

0.702

AC:

31302

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7790

AN:

25756

East Asian (EAS)

AF:

0.892

AC:

35200

AN:

39444

South Asian (SAS)

AF:

0.599

AC:

50960

AN:

85134

European-Finnish (FIN)

AF:

0.420

AC:

22364

AN:

53202

Middle Eastern (MID)

AF:

0.350

AC:

1982

AN:

5666

European-Non Finnish (NFE)

AF:

0.393

AC:

417572

AN:

1063312

Other (OTH)

AF:

0.455

AC:

26649

AN:

58548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

17122

34244

51366

68488

85610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13204

26408

39612

52816

66020

<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:

0.543

AC:

82474

AN:

151902

Hom.:

25054

Cov.:

AF XY:

0.549

AC XY:

40730

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.784

AC:

32491

AN:

41460

American (AMR)

AF:

0.587

AC:

8956

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1029

AN:

3464

East Asian (EAS)

AF:

0.881

AC:

4547

AN:

5160

South Asian (SAS)

AF:

0.608

AC:

2924

AN:

4806

European-Finnish (FIN)

AF:

0.417

AC:

4391

AN:

10530

Middle Eastern (MID)

AF:

0.295

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.393

AC:

26720

AN:

67910

Other (OTH)

AF:

0.506

AC:

1064

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1669

3338

5007

6676

8345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.328

Hom.:

1322

Bravo

AF:

0.566

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Leber congenital amaurosis 2 (1)

not specified (1)

Retinitis pigmentosa 20 (1)

Retinitis pigmentosa 87 with choroidal involvement (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.39

(source)

DANN

Benign

0.56

PhyloP100

-1.5

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