chr20-44622588-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_SupportingPM3_StrongPVS1_StrongPP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.845G>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 282 (p.Arg282Gln). This variant is considered in the PVS1 criteria based on experimental evidence indicating that it has the effect of affecting the splicing site. In line with the predictions of splicing algorithms, experimental validation (from Dr. Mike Hershfield - Internal Communication) has established that the variant occurs at the splice junction between exon 9 and intron 10 and has been shown to cause aberrant splicing in peripheral blood leukocytes (PBL) of a female Arab patient with ADA-SCID. Based on this, we classify PVS1 at a Strong level, as it results in the loss of more than 10% of the protein, and other pathogenic variants have already been described downstream (e.g., NM_000022.4(ADA):c.870C>A (p.Tyr290Ter), Pathogenic according to SCID VCEP specifications).The highest population minor allele frequency in gnomAD v4 is 0.000005310 (12/1180048 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). PMID:19830125: 14-month-old Arab boy: Family history of SCID 0.5pts + T-B-NK- profile 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + Reduced ADA enzyme activity 1pt, total=2.5 pts, PP4_Moderate. PMID:32307643, Patients 3 and 25, both are homozygous, reaching the maximum of 1 point for homozygous occurrence. From the same report, patient 2: Compound heterozygous,c.221G>T, p.G74V, Likely Pathogenic according to SCID VCEP specifications; 1 point. Total 2 points, PM3_Strong.In summary, this variant meets the criteria to be classified as Pathogenic for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1_Strong, PM2_Supporting, PP4_Moderate, and PM3_Strong. (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9871496/MONDO:0007064/114
Frequency
Consequence
NM_000022.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.845G>A | p.Arg282Gln | missense_variant, splice_region_variant | 9/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.773G>A | p.Arg258Gln | missense_variant, splice_region_variant | 8/11 | ||
ADA | NM_001322050.2 | c.440G>A | p.Arg147Gln | missense_variant, splice_region_variant | 8/11 | ||
ADA | NR_136160.2 | n.872+241G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.845G>A | p.Arg282Gln | missense_variant, splice_region_variant | 9/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251334Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 24, 2017 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 23, 2024 | The c.845G>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 282 (p.Arg282Gln). This variant is considered in the PVS1 criteria based on experimental evidence indicating that it has the effect of affecting the splicing site. In line with the predictions of splicing algorithms, experimental validation (from Dr. Mike Hershfield - Internal Communication) has established that the variant occurs at the splice junction between exon 9 and intron 10 and has been shown to cause aberrant splicing in peripheral blood leukocytes (PBL) of a female Arab patient with ADA-SCID. Based on this, we classify PVS1 at a Strong level, as it results in the loss of more than 10% of the protein, and other pathogenic variants have already been described downstream (e.g., NM_000022.4(ADA):c.870C>A (p.Tyr290Ter), Pathogenic according to SCID VCEP specifications). The highest population minor allele frequency in gnomAD v4 is 0.000005310 (12/1180048 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). PMID: 19830125: 14-month-old Arab boy: Family history of SCID 0.5pts + T-B-NK- profile 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + Reduced ADA enzyme activity 1pt, total=2.5 pts, PP4_Moderate. PMID: 32307643, Patients 3 and 25, both are homozygous, reaching the maximum of 1 point for homozygous occurrence. From the same report, patient 2: Compound heterozygous,c.221G>T, p.G74V, Likely Pathogenic according to SCID VCEP specifications; 1 point. Total 2 points, PM3_Strong. In summary, this variant meets the criteria to be classified as Pathogenic for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1_Strong, PM2_Supporting, PP4_Moderate, and PM3_Strong. (VCEP specifications version 1.0). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the ADA protein (p.Arg282Gln). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs751635016, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of adenosine deaminase deficiency (PMID: 19179314, 19830125, 27129325; Invitae). 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: 402341). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 19, 2018 | Variant summary: ADA c.845G>A (p.Arg282Gln) results in a conservative amino acid change located in the Adenosine/AMP deaminase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant is located in the last nucleotide of exon 9, suggesting it may interfere with proper splicing. 5/5 in silico prediction tools predict that the variant abolishes or weakens the 5' donor site. However, these predictions have yet to be tested in functional studies. The variant allele was found at a frequency of 7.2e-06 in 277232 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (7.2e-06 vs 0.0016), allowing no conclusion about variant significance. The variant, c.845G>A, has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome, both as a homozygous and compound heterozygous allele (Aiuti_2009, Hellani_2009, Sauer_2012). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating ADA activity in patient blood mononuclear cells, which showed <10% of normal activity compared to healthy controls (Aiuti_2009). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance," however, a disclaimer is included in the description stating that the variant has not undergone full assessment. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in1 homozygous arab boy with severe combined immunodeficiency (Hellani-2009) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at