rs281865195
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2
The NM_014336.5(AIPL1):c.1053_1064delTGCAGAGCCACC(p.Ala352_Pro355del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,613,036 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014336.5 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000625 AC: 95AN: 151970Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000872 AC: 218AN: 250120Hom.: 0 AF XY: 0.000776 AC XY: 105AN XY: 135274
GnomAD4 exome AF: 0.000717 AC: 1047AN: 1460948Hom.: 2 AF XY: 0.000695 AC XY: 505AN XY: 726818
GnomAD4 genome AF: 0.000625 AC: 95AN: 152088Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39AN XY: 74358
ClinVar
Submissions by phenotype
CONE-ROD DYSTROPHY, AIPL1-RELATED Pathogenic:1Uncertain:1
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NM_014336.3:c.1053_1064delTGCAGAGCCACC in the AIPL1 gene has an allele frequency of 0.01 in Ashkenazi Jewish subpopulation in the gnomAD database. It has been detected in two individuals with cone-rod dystrophy (PMID: 10873396). This in-frame deletion happens in a repetitive region without known function. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP3, PP4. -
not provided Benign:1Other:1
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Juvenile retinitis pigmentosa, AIPL1-related Pathogenic:1
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not specified Uncertain:1
Variant summary: AIPL1 c.1053_1064del12 (p.Ala352_Pro355del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The variant allele was found at a frequency of 0.00087 in 250120 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AIPL1 causing Leber Congenital Amaurosis (0.00087 vs 0.0011), allowing no conclusion about variant significance. Although reported in the literature, as unlikely to be associated with autosomal dominant Inherited Retinal Degeneration (example, Hanany_2019), to our knowledge, no penetrant association of c.1053_1064del12 in individuals affected with Autosomal Recessive Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
AIPL1-related disorder Uncertain:1
The AIPL1 c.1053_1064del12 variant is predicted to result in an in-frame deletion (p.Ala352_Pro355del). This variant has been reported in the heterozygous state in individuals with autosomal dominant cone-rod dystrophy or juvenile retinitis pigmentosa (Sohocki et al. 2000. PubMed ID: 10873396; Sacristan-Reviriego et al. 2020. PubMed ID: 33067476). This deletion is located in the highly conserved "hinge region" of AIPL1, which is only present in primates (Sohocki et al. 2000. PubMed ID: 10873396). A transgenic mouse model has demonstrated a dominant negative effect on photoreceptors, leading to cone degeneration (Ku et al. 2015. PubMed ID: 25274777). In vitro functional studies revealed that this variant does not affect its cytoplasmic distribution, interaction with HSP90 or cGMP modulation; however these studies are not known to be informative for modeling of gain-of-function disease mechanisms (Sacristan-Reviriego et al 2020. PubMed ID: 33067476). Additionally, this variant is reported in 1.0% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which is likely too frequent to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Retinal dystrophy Uncertain:1
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Leber congenital amaurosis 4 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at