rs587777241
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001282225.2(ADA2):āc.336C>Gā(p.His112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,453,262 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H112Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001282225.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA2 | NM_001282225.2 | c.336C>G | p.His112Gln | missense_variant | 3/10 | ENST00000399837.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA2 | ENST00000399837.8 | c.336C>G | p.His112Gln | missense_variant | 3/10 | 1 | NM_001282225.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250956Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135628
GnomAD4 exome AF: 0.0000351 AC: 51AN: 1453262Hom.: 0 Cov.: 31 AF XY: 0.0000374 AC XY: 27AN XY: 721038
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Vasculitis due to ADA2 deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 112 of the ADA2 protein (p.His112Gln). This variant is present in population databases (rs587777241, gnomAD 0.004%). This missense change has been observed in individual(s) with ADA2-deficiency and early-onset stroke and polyarteritis nodosa (PMID: 24552284, 28493328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 120302). 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%. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552284). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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. Significant phenotypic variability within families has been noted, with some asymptomatic individuals reported despite low enzyme levels (PMID: 27059682, 24552285). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 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 an annotated Zinc binding site (Pfam). (I) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(His112Tyr) variant was identified in an individual with ADA2 deficiency (PMID: 32892503). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with ADA2 deficiency in ClinVar and the literature (PMID: 30559313, 27444081, 28493328, 24552284). The phenotypes reported in these individuals were variable and included skin manifestations, immunodeficiency, neuropathy, anaemia, and stroke. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Affected individuals with this variant have low ADA2 enzyme activity, and this variant variant is unable to phenotypically rescue transgenic zebrafish (PMID: 24552284, 30559313, 27444081). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 06, 2014 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 09, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2023 | Published functional studies in zebrafish embryos demonstrate a damaging effect on protein function (Zhou et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28974505, 34324127, 34004258, 24552284, 30559313, 28493328, 27444081) - |
Autoinflammatory syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at