rs281865195
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BP6BS2
The NM_014336.5(AIPL1):c.1053_1064del(p.Ala352_Pro355del) variant causes a 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
Genomes: 𝑓 0.00062 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00072 ( 2 hom. )
Consequence
AIPL1
NM_014336.5 inframe_deletion
NM_014336.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.38
Genes affected
AIPL1 (HGNC:359): (aryl hydrocarbon receptor interacting protein like 1) Leber congenital amaurosis (LCA) is the most severe inherited retinopathy with the earliest age of onset and accounts for at least 5% of all inherited retinal diseases. Affected individuals are diagnosed at birth or in the first few months of life with nystagmus, severely impaired vision or blindness and an abnormal or flat electroretinogram. The photoreceptor/pineal-expressed gene, AIPL1, encoding aryl-hydrocarbon interacting protein-like 1, is located within the LCA4 candidate region. The encoded protein contains three tetratricopeptide motifs, consistent with chaperone or nuclear transport activity. Mutations in this gene may cause approximately 20% of recessive LCA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_014336.5.
BP6
?
Variant 17-6425550-GGGTGGCTCTGCA-G is Benign according to our data. Variant chr17-6425550-GGGTGGCTCTGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5568.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, not_provided=1, Likely_benign=1}.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIPL1 | NM_014336.5 | c.1053_1064del | p.Ala352_Pro355del | inframe_deletion | 6/6 | ENST00000381129.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIPL1 | ENST00000381129.8 | c.1053_1064del | p.Ala352_Pro355del | inframe_deletion | 6/6 | 1 | NM_014336.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000625 AC: 95AN: 151970Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000872 AC: 218AN: 250120Hom.: 0 AF XY: 0.000776 AC XY: 105AN XY: 135274
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GnomAD4 exome AF: 0.000717 AC: 1047AN: 1460948Hom.: 2 AF XY: 0.000695 AC XY: 505AN XY: 726818
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GnomAD4 genome ? AF: 0.000625 AC: 95AN: 152088Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39AN XY: 74358
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
CONE-ROD DYSTROPHY, AIPL1-RELATED Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2000 | - - |
Uncertain significance, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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
not provided, no classification provided | literature only | Retina International | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Juvenile retinitis pigmentosa, AIPL1-related Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2000 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 12, 2022 | 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. - |
Leber congenital amaurosis 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at