rs200930463
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001282225.2(ADA2):c.140G>T(p.Gly47Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G47A) has been classified as Pathogenic.
Frequency
Consequence
NM_001282225.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA2 | NM_001282225.2 | c.140G>T | p.Gly47Val | missense_variant | 2/10 | ENST00000399837.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA2 | ENST00000399837.8 | c.140G>T | p.Gly47Val | missense_variant | 2/10 | 1 | NM_001282225.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251366Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135884
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461454Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22AN XY: 727040
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Observed with a second variant in the ADA2 gene, including multiple instances of a different pathogenic variant confirmed on the opposite allele (in trans), in unrelated patients with features consistent with ADA2 deficiency in published literature (Navon Elkan et al., 2014; Hashem et al., 2017; zen et al., 2020; Hashem et al., 2021; Yap et al., 2021); Published functional studies demonstrate a damaging effect: decreased expression of mutant protein (Navon Elkan et al., 2014); 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: 34004258, 32531373, 31043544, 28522451, 28974505, 34324127, 24552285, 34657246) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 22, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Vasculitis due to ADA2 deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120306). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120301,VCV000120304,VCV001076271, PMID:24552284,29600946,24737293). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.909>=0.6, 3CNET: 0.896>=0.75). A missense variant is a common mechanism associated with Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with vasculitis due to ADA2 deficiency (MONDO:0014306). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported (PMID: 24552285). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (30 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated A_deaminase_N domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These alternative changes, p.(Gly47Ala), p.(Gly47Trp) and p.(Gly47Arg), have been reported multiple times as likely pathogenic and pathogenic (ClinVar, PMID: 34324127). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in both homozygous and compound heterozygous individuals with primary immunodeficiency or ADA2 deficiency (ClinVar, PMID: 34324127, PMID: 32531373). (SP) 1205 - This variant has been shown to be maternally inherited (by Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 06, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 02, 2023 | This missense change has been observed in individuals with clinical features of ADA2-related conditions (PMID: 24552285, 28974505, 31043544; Invitae). This variant is present in population databases (rs200930463, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the ADA2 protein (p.Gly47Val). ClinVar contains an entry for this variant (Variation ID: 120306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24552285, 26914925, 27059682, 28830446). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 17, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at