rs114025668
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000022.4(ADA):c.643G>A(p.Ala215Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,614,108 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A215A) has been classified as Likely benign.
Frequency
Consequence
NM_000022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.643G>A | p.Ala215Thr | missense_variant | 7/12 | ENST00000372874.9 | |
ADA | NM_001322050.2 | c.238G>A | p.Ala80Thr | missense_variant | 6/11 | ||
ADA | NM_001322051.2 | c.607-112G>A | intron_variant | ||||
ADA | NR_136160.2 | n.735G>A | non_coding_transcript_exon_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.643G>A | p.Ala215Thr | missense_variant | 7/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251422Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135890
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461828Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 727210
GnomAD4 genome ? AF: 0.000276 AC: 42AN: 152280Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20AN XY: 74454
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Uncertain:6Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 26, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 215 of the ADA protein (p.Ala215Thr). This variant is present in population databases (rs114025668, gnomAD 0.07%). This missense change has been observed in individual(s) with partial ADA deficiency without SCID (PMID: 2166947, 9108404, 9225964, 9758612, 14499267). ClinVar contains an entry for this variant (Variation ID: 1967). 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 ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 2166947, 9108404, 9361033, 11067872). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Partial adenosine deaminase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1990 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2020 | Variant summary: ADA c.643G>A (p.Ala215Thr) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing resulting in induction of exon 7 skipping in approximately 50% of cells (Ozsahin_1997) but a residual low level (10-15%) skipping of exon 7 was also observed in normal cells. Therefore, the exact impact of this splicing phenomenon on ADA activity in-vivo is not clear. The variant allele was found at a frequency of 9.9e-05 in 251422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (9.9e-05 vs 0.0014), allowing no conclusion about variant significance. c.643G>A has been not been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome, but has been observed in clinically asymptomatic individuals presenting with a partial ADA deficiency in-vitro (example, Hirschhorn_1990, Hirschhorn_1997, Ozsahin_1997). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal ADA enzyme activity (example, Jiang_1997, Richard_2007, Arredondo-Vega_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at