rs121908718
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPM3PS3_SupportingPP4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu).The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported.This variant was described in at least one patient in the literature, who presents *Reduced ADA enzyme activity in patient cells (1pt); *Reported also reported "a definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID:34975878).The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence.In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA9871472/MONDO:0007064/114
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.890C>T | p.Pro297Leu | missense_variant | 10/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.818C>T | p.Pro273Leu | missense_variant | 9/11 | ||
ADA | NM_001322050.2 | c.485C>T | p.Pro162Leu | missense_variant | 9/11 | ||
ADA | NR_136160.2 | n.917C>T | non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.890C>T | p.Pro297Leu | missense_variant | 10/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251492Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727238
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2023 | 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. This variant disrupts the p.Pro297 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2166947, 2783588). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt ADA protein function. ClinVar contains an entry for this variant (Variation ID: 1505857). This missense change has been observed in individual(s) with clinical features of ADA-related conditions (PMID: 34975878). This variant is present in population databases (rs121908718, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the ADA protein (p.Pro297Leu). - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 23, 2024 | The c.890C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause the substitution of Proline by Leucine at amino acid 297 (p.Pro297Leu). The highest population minor allele frequency in gnomAD v4 is 0.000008350 (2/44896 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous was reported. This variant was described in at least one patient in the literature, who presents *Reduced ADA enzyme activity in patient cells (1pt); *Reported also reported "a definite increase in intracellular metabolites" (dAdo nucleotides), (2 pts); *SCID gene panel or exome/genome sequencing conducted (0.5pt). Total 3.5 points, PP4_Moderate (PMID: 34975878). The variant expression in E. Coli falls into our activity Group III (Dr. Hershfield - internal communication). PS3 is met at the Supporting level of evidence. In summary, this variant is classified as Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Moderate, and PS3_Supporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at