rs374974565
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001282225.2(ADA2):c.1069G>A(p.Ala357Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,374 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A357A) has been classified as Likely benign.
Frequency
Consequence
NM_001282225.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA2 | NM_001282225.2 | c.1069G>A | p.Ala357Thr | missense_variant | 7/10 | ENST00000399837.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA2 | ENST00000399837.8 | c.1069G>A | p.Ala357Thr | missense_variant | 7/10 | 1 | NM_001282225.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251158Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135740
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461166Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726940
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Vasculitis due to ADA2 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 357 of the ADA2 protein (p.Ala357Thr). This variant is present in population databases (rs374974565, gnomAD 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (DADA2) (PMID: 31008556). ClinVar contains an entry for this variant (Variation ID: 582418). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ADA2 function (PMID: 34004258). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 01, 2021 | - - |
ADA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 27, 2023 | The ADA2 c.1069G>A variant is predicted to result in the amino acid substitution p.Ala357Thr. This variant was reported in the homozygous state in an individual with childhood-onset polyarteritis nodosa (See patient 4 in Gibson et al 2019. PubMed ID: 31008556). A serum sample from this patient indicated a significant loss of ADA enzyme activity in comparison to controls (Gibson et al 2019. PubMed ID: 31008556). Additional functional studies also support that this variant results in reduced enzyme activity (Jee H et al 2021. PubMed ID: 34004258). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-17669241-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at