22-17209539-C-G
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001282225.2(ADA2):āc.139G>Cā(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,982 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 Pathogenic (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. 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 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA2 | NM_001282225.2 | c.139G>C | p.Gly47Arg | missense_variant | 2/10 | ENST00000399837.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA2 | ENST00000399837.8 | c.139G>C | p.Gly47Arg | missense_variant | 2/10 | 1 | NM_001282225.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251330Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135870
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
Vasculitis due to ADA2 deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the ADA2 protein (p.Gly47Arg). This variant is present in population databases (rs202134424, gnomAD 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 24552285, 24737293, 25075844, 27059682, 28522451, 28830446, 31008556, 31291964). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1076271). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | ADA2: PM3:Strong, PS1, PM1, PM2, PM5 - |
Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
Autoinflammatory syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 06, 2021 | - - |
ADA2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2023 | The ADA2 c.139G>C variant is predicted to result in the amino acid substitution p.Gly47Arg. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with ADA2-related disease (see for example - Nanthapisal et al. 2016. PubMed ID: 27059682; Skrabl-Baumgartner et al. 2017. PubMed ID: 28830446). Functional studies found this variant results in <20% of wild type activity (Jee et al. 2021. PubMed ID: 34004258). Additionally, an alternate nucleotide substitution (c.139G>A) resulting in the same missense variant and alternate missense variants affecting this residue (p.Gly47Trp, p.Gly47Ala, p.Gly47Val) have been reported as pathogenic (Karacan et al. 2019. PubMed ID: 30783801; Jee et al. 2021. PubMed ID: 34004258). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-17690429-C-G). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at