rs199422328
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000022.4(ADA):c.221G>T(p.Gly74Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000022.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.221G>T | p.Gly74Val | missense_variant, splice_region_variant | 4/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.221G>T | p.Gly74Val | missense_variant, splice_region_variant | 4/11 | ||
ADA | NM_001322050.2 | c.-69G>T | splice_region_variant, 5_prime_UTR_variant | 4/11 | |||
ADA | NR_136160.2 | n.313G>T | splice_region_variant, non_coding_transcript_exon_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.221G>T | p.Gly74Val | missense_variant, splice_region_variant | 4/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727188
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74338
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 23, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 23, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 74 of the ADA protein (p.Gly74Val). This variant is present in population databases (rs199422328, gnomAD 0.03%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8614422, 27129325; Invitae). ClinVar contains an entry for this variant (Variation ID: 1977). 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 disruptive. Experimental studies have shown that this missense change affects ADA function (PMID: 8614422, 9758612). This variant disrupts the p.Gly74 amino acid residue in ADA. Other variant(s) that disrupt this residue have been observed in individuals with ADA-related conditions (PMID: 30290665), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 12, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at