rs121908721
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000022.4(ADA):c.872C>T(p.Ser291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S291W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.872C>T | p.Ser291Leu | missense_variant | 10/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.800C>T | p.Ser267Leu | missense_variant | 9/11 | ||
ADA | NM_001322050.2 | c.467C>T | p.Ser156Leu | missense_variant | 9/11 | ||
ADA | NR_136160.2 | n.899C>T | non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.872C>T | p.Ser291Leu | missense_variant | 10/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251496Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135922
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727246
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:8Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 291 of the ADA protein (p.Ser291Leu). This variant is present in population databases (rs121908721, gnomAD 0.01%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1284479, 26255240, 26376800). ClinVar contains an entry for this variant (Variation ID: 1971). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 06, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at