ClinVar Genomic variation as it relates to human health

PVS1, PP1_strong, PS4_moderate, PP4

ADA2 c.973-2A>G has been identified in the homozygous and compound heterozygous state in multiple individuals with ADA2 deficiency and has been reported in ClinVar (Variation ID: 541735). This ADA2 variant (rs139750129) is rare (<0.1%) in a large population dataset (gnomAD: 37/282072 total alleles; 0.01312%; no homozygotes). Bioinformatic analysis predicts that this splice site variant will destroy the intron 5 canonical acceptor site and cause abnormal gene splicing. Two studies confirm that this variant is associated with ADA2 missplicing. We consider ADA2 c.973-2A>G to be pathogenic.

ACMG classification criteria: PVS1 very strong, PM2 supporting, PM3 very strong, PP1 supporting

Variant summary: CECR1 c.973-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.00012 in 250678 control chromosomes (gnomAD). c.973-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Deficiency of adenosine deaminase-2 (example: Andriessen_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 37277582). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change affects an acceptor splice site in intron 6 of the ADA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). This variant is present in population databases (rs139750129, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with antibody deficiencies and vasculopathy (PMID: 28493328, 29963054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 541735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate a damaging effect. This splice site variant destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation (PMID: 29963054); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31393689, 31856934, 29391253, 28983775, 30386947, 29681619, 28493328, 31617030, 32535845, 34039731, 29963054)

The ADA2 c.973-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the compound heterozygous or homozygous state in multiple individuals with antibody deficiency with vascular manifestations (Schepp et al. 2017. PubMed ID: 28493328; Trotta et al. 2018. PubMed ID: 29391253; Springer et al. 2018. PubMed ID: 29963054; Chong-Neto et al. 2019. PubMed ID: 31617030; van Well et al. 2019. PubMed ID: 31856934; Ganhão et al. 2020. PubMed ID: 32535845). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in ADA2 are expected to be pathogenic. This variant is interpreted as pathogenic.