Genetic Variant RPE65:c.*341T>C (chr1-68429435-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000329.3(RPE65):c.*341T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 283,492 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0082 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 2 hom. )

Consequence

RPE65
NM_000329.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.497

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-68429435-A-G is Benign according to our data. Variant chr1-68429435-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 875991.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00817 (1244/152278) while in subpopulation AFR AF = 0.028 (1163/41556). AF 95% confidence interval is 0.0267. There are 12 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

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.*341T>C	3_prime_UTR	Exon 14 of 14	NP_000320.1	Q16518
RPE65	NM_001406853.1		c.*341T>C	3_prime_UTR	Exon 13 of 13	NP_001393782.1
RPE65	NM_001406856.1		c.*341T>C	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.*341T>C	3_prime_UTR	Exon 14 of 14	ENSP00000262340.5	Q16518
RPE65	ENST00000713936.1		n.*1848T>C	non_coding_transcript_exon	Exon 15 of 15	ENSP00000519233.1	A0AAQ5BH58
RPE65	ENST00000713937.1		n.*1091T>C	non_coding_transcript_exon	Exon 13 of 13	ENSP00000519234.1	A0AAQ5BH46

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1243

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00622

GnomAD4 exome

AF:

0.000823

AC:

108

AN:

131214

Hom.:

Cov.:

AF XY:

0.000707

AC XY:

AN XY:

70758

show subpopulations

African (AFR)

AF:

0.0272

AC:

AN:

2944

American (AMR)

AF:

0.00140

AC:

AN:

5004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3310

East Asian (EAS)

AF:

0.00

AC:

AN:

5304

South Asian (SAS)

AF:

0.0000456

AC:

AN:

21918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

492

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

79358

Other (OTH)

AF:

0.00251

AC:

AN:

6778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

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:

0.00817

AC:

1244

AN:

152278

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

595

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0280

AC:

1163

AN:

41556

American (AMR)

AF:

0.00425

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

131

197

262

328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00755

Hom.:

Bravo

AF:

0.00943

Asia WGS

AF:

0.000868

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 2 (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.50

Mutation Taster

=100/0

polymorphism

(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