20-44621082-A-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000022.4(ADA):āc.911T>Gā(p.Leu304Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,104 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 (ā ā ).
Frequency
Consequence
NM_000022.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ADA | NM_000022.4 | c.911T>G | p.Leu304Arg | missense_variant | Exon 10 of 12 | ENST00000372874.9 | NP_000013.2 | |
ADA | NM_001322051.2 | c.839T>G | p.Leu280Arg | missense_variant | Exon 9 of 11 | NP_001308980.1 | ||
ADA | NM_001322050.2 | c.506T>G | p.Leu169Arg | missense_variant | Exon 9 of 11 | NP_001308979.1 | ||
ADA | NR_136160.2 | n.938T>G | non_coding_transcript_exon_variant | Exon 9 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.911T>G | p.Leu304Arg | missense_variant | Exon 10 of 12 | 1 | NM_000022.4 | ENSP00000361965.4 | ||
ADA | ENST00000695995.1 | c.521T>G | p.Leu174Arg | missense_variant | Exon 7 of 9 | ENSP00000512318.1 | ||||
ADA | ENST00000695991.1 | c.449T>G | p.Leu150Arg | missense_variant | Exon 6 of 8 | ENSP00000512314.1 | ||||
ADA | ENST00000695956.1 | c.65T>G | p.Leu22Arg | missense_variant | Exon 1 of 3 | ENSP00000512285.1 | ||||
ADA | ENST00000696038.1 | n.*668T>G | non_coding_transcript_exon_variant | Exon 8 of 9 | ENSP00000512344.1 | |||||
ADA | ENST00000696038.1 | n.*668T>G | 3_prime_UTR_variant | Exon 8 of 9 | ENSP00000512344.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251496Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135922
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727248
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:5
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NM_000022.2(ADA):c.911T>G(L304R) is a missense variant classified as likely pathogenic in the context of adenosine deaminase deficiency. L304R has been observed in cases with relevant disease (PMID: 17185467, 1346349). Functional assessments of this variant are available in the literature (PMID: 3007108). L304R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.911T>G(L304R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the ADA protein (p.Leu304Arg). This variant is present in population databases (rs199422327, gnomAD 0.008%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 46025, 1284479, 17185467). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1006T>G. ClinVar contains an entry for this variant (Variation ID: 1958). Invitae Evidence 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 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: 3007108). For these reasons, this variant has been classified as Pathogenic. -
ADA-related disorder Pathogenic:1
The ADA c.911T>G variant is predicted to result in the amino acid substitution p.Leu304Arg. This variant has been reported in an individual with adenosine deaminase deficiency; however, a second pathogenic variant was not identified (Valerio et al. 1986. PubMed ID: 3007108). It has been reported in the compound heterozygous state in individuals with adenosine deaminase deficiency (Table S7, Bell et al. 2011. PubMed ID: 21228398; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). In vitro and in situ functional studies demonstrate this variant alters restriction sites, reduces hydrophobic properties, and produces a protein lacking catalytic activity (Valerio et al. 1986. PubMed ID: 3007108; Rojas-Restrepo et al. 2021. PubMed ID: 34975878). This variant is reported in 0.0097% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
PP3, PM1, PM2, PM3, PS3_supporting, PS4_moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at