Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000265602.11(AHI1):c.3503A>G(p.Glu1168Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,613,824 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1168E) has been classified as Likely benign.
AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]
Computational evidence support a benign effect (MetaRNN=0.007654071).
BP6
Variant 6-135290508-T-C is Benign according to our data. Variant chr6-135290508-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 388935.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
Uncertain significance, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Oct 31, 2018
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Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Oct 13, 2017
A variant of uncertain significance has been identified in the AHI1 gene. The E1168G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports E1168G was observed in 25/8242 (0.3%) alleles from individuals of European background, and the 1000 Genomes Project reports E1168G was observed in 1/198 (0.5%) alleles from individuals of Western European ancestry living in Utah. The E1168G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Likely benign, no assertion criteria provided
clinical testing
Genetic Services Laboratory, University of Chicago
Sep 14, 2022
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Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria provided
clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Jan 01, 2019
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Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Jan 01, 2023
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not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Sep 01, 2022
AHI1: BP4 -
Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 29, 2024
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AHI1-related disorder Benign:1
Likely benign, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
Feb 03, 2022
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -