rs398122822
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001111.5(ADAR):c.3019G>A(p.Gly1007Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_001111.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAR | NM_001111.5 | c.3019G>A | p.Gly1007Arg | missense_variant, splice_region_variant | 11/15 | ENST00000368474.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAR | ENST00000368474.9 | c.3019G>A | p.Gly1007Arg | missense_variant, splice_region_variant | 11/15 | 1 | NM_001111.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461336Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726956
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Aicardi-Goutieres syndrome 6 Pathogenic:11Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 30, 2020 | This ADAR variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in at least eleven individuals from nine families with autosomal dominant Aicardi-Goutieres syndrome. In four families, the c.3019G>A variant occurred de novo. Independent functional studies have shown that the p.Gly1007Arg substitution inhibits the RNA editing activity of ADAR1, presumably through steric hindrance at the base-flipping step of the deaminase reaction. We consider this variant to be pathogenic. - |
Likely pathogenic, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 27, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2024 | heterozygous - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 11, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 17, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Mar 01, 2024 | The NM_001111.5: c.3019G>A variant is located in exon 11 of the ADAR gene. This variant involves a change at the protein level from Glycine to Arginine at position 1007 (p.(Gly1007Arg)). This position is highly conserved and corresponds to a well-established domain of the protein. This variant has a null frequency in population databases and, in turn, has numerous reports in ClinVar, where it is classified as likely pathogenic/pathogenic (ClinVarID: 39458). In addition, more than 4 cases have been reported in which the variant was found 'de novo' (PMID: 23001123, 33307271). On the other hand, bioinformatic tools predict that the variant would be deleterious, which agrees with what has been demonstrated through functional studies (PMID: 25243380, 26372505). It is important to highlight that, although patients with the AGS phenotype associated with an autosomal recessive inheritance pattern have been described, this particular variant behaves as dominant-negative, so affected patients are heterozygous for said variant. (PS3supporting, PM1supporting, PM2moderate, PM6strong, PP3moderate) - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wangler Lab, Baylor College of Medicine | - | This ADAR variant at c.3019G>A (p.G1007R) was seen on exome through the Texome project (R01HG011795). This variant has been described as a de novo variant in the heterozygous state in individuals with autosomal dominant Aicardi-Goutières syndrome (PMID: 23001123, 33307271) and in individuals with dyschromatosis symmetrica hereditaria with additional features including dystonia, mental deterioration and brain MRI abnormalities (PMID: 16817193, 19017046). In addition, this heterozygous variant has been described in two individuals with tremors, spasticity/dystonia, abnormal MRI findings and progressive motor deterioration (PMID: 24262145, 29691679) and two internal cases with a similar phenotype. This variant is absent from gnomAD (PM2). Functional studies suggest this variant showed a significant effect on editing function of the protein, with levels of editing equivalent to those seen with inactive protein (PMID: 23001123) (PS3). This heterozygous variant shows RNA editing deficiency similar to Aicardi-Goutières associated variants and more severely affected when compared to dyschromatosis symmetrica hereditaria associated variants (PMID: 26802932).This variant lies at the last nucleotide of exon 11 (of 15) for the reported transcript. This variant is predicted to be deleterious(CADD: 34.000, SpliceAI: 0.190) (PP3). The evolutionary conservation of this residue is high. Variant is located in the adenosinede aminase/editase domain (PMID: 23001123). We classify this variant as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.G1007R in ADAR (NM_001111.5) has been previously reported in multiple individuals with dominant Aicardi Goutieres syndrome (Kondo T et al,2008). Functional analysis revealed a damagig effect (Fisher AJ et al,2017). The variant has been submitted to ClinVar as Pathogenic. The p.G1007R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1007R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3019 in ADAR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Symmetrical dyschromatosis of extremities;C3539013:Aicardi-Goutieres syndrome 6 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Jun 28, 2022 | Criteria Codes: PS3 PS4_Mod PM2 PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change affects ADAR function (PMID: 26802932, 29775506). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39458). This missense change has been observed in individual(s) with clinical features of autosomal dominant dyschromatosis symmetrica hereditaria and/or autosomal dominant Aicardi Goutieres syndrome (PMID: 15955093, 16817193, 19017046, 23001123, 24262145, 25243380, 28561207, 29691679, 32801363, 33307271). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1007 of the ADAR protein (p.Gly1007Arg). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ADAR: PS2, PM2, PS4:Moderate, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2022 | Reported in published literature in multiple affected individuals from a few unrelated families with dyschromatosis symmetrica hereditaria and neurodegeneration with dystonia and intracranial calcification. Also present in multiple unaffected relatives in these families, suggesting G1007R may exhibit incomplete penetrance (Suzuki et al., 2005; Kondo et al., 2008); Published functional studies suggest that G1007R may confer a dominant-negative effect by binding more tightly to RNA and acting as competitive inhibitor to the wild-type protein (Rice et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29775506, 24262145, 25243380, 19017046, 16817193, 27959697, 15955093, 23001123, 29691679, 31737037, 34426522, 32801363, 33307271, 27535533) - |
Symmetrical dyschromatosis of extremities Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | May 14, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at