chr1-68431318-C-T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000329.3(RPE65):c.1302G>A(p.Ala434=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,908 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A434A) has been classified as Likely benign.
Frequency
Consequence
NM_000329.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPE65 | NM_000329.3 | c.1302G>A | p.Ala434= | synonymous_variant | 12/14 | ENST00000262340.6 | |
LOC124904198 | XR_007066164.1 | n.71+11197C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPE65 | ENST00000262340.6 | c.1302G>A | p.Ala434= | synonymous_variant | 12/14 | 1 | NM_000329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00823 AC: 1252AN: 152126Hom.: 12 Cov.: 32
GnomAD3 exomes AF: 0.00224 AC: 562AN: 250846Hom.: 6 AF XY: 0.00164 AC XY: 222AN XY: 135524
GnomAD4 exome AF: 0.000882 AC: 1289AN: 1461664Hom.: 17 Cov.: 32 AF XY: 0.000843 AC XY: 613AN XY: 727128
GnomAD4 genome ? AF: 0.00823 AC: 1253AN: 152244Hom.: 12 Cov.: 32 AF XY: 0.00809 AC XY: 602AN XY: 74422
ClinVar
Submissions by phenotype
Leber congenital amaurosis 2;C3151086:Retinitis pigmentosa 20 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Nov 10, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
RPE65-related recessive retinopathy Benign:1
Benign, reviewed by expert panel | curation | ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen | Dec 22, 2023 | NM_000329.3(RPE65):c.1302G>A (p.Ala434=) is a synonymous variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.02695, with 734 alleles / 24954 total alleles and 7 homozygotes in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.07 for donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). - |
Leber congenital amaurosis Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Leber congenital amaurosis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Retinitis pigmentosa Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at