20-44626517-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000022.4(ADA):c.301C>G(p.Arg101Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,850 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000022.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.301C>G | p.Arg101Gly | missense_variant | 4/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.301C>G | p.Arg101Gly | missense_variant | 4/11 | ||
ADA | NM_001322050.2 | c.12C>G | p.Cys4Trp | missense_variant | 4/11 | ||
ADA | NR_136160.2 | n.393C>G | non_coding_transcript_exon_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.301C>G | p.Arg101Gly | missense_variant | 4/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | 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.Arg101 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1974554, 3182793, 9758612). 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 expected to disrupt ADA protein function. ClinVar contains an entry for this variant (Variation ID: 971097). This variant has not been reported in the literature in individuals affected with ADA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 101 of the ADA protein (p.Arg101Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at