NM_000026.4:c.1400C>G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000026.4(ADSL):āc.1400C>Gā(p.Pro467Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,216 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000026.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADSL | ENST00000623063.3 | c.1400C>G | p.Pro467Arg | missense_variant | Exon 13 of 13 | 1 | NM_000026.4 | ENSP00000485525.1 | ||
ENSG00000284431 | ENST00000639722.1 | n.*1096C>G | non_coding_transcript_exon_variant | Exon 12 of 31 | 5 | ENSP00000492828.1 | ||||
ENSG00000284431 | ENST00000639722.1 | n.*1096C>G | 3_prime_UTR_variant | Exon 12 of 31 | 5 | ENSP00000492828.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251416Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461216Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726970
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The P467R variant in the ADSL gene has been reported previously in the presence of a second ADSL missense variant in an individual with Type 1 adenylsuccinate lyase deficiency (Spiegel et al, 2006; Zikanova et al., 2010). The P467R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P467R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret P467R as a likely pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Adenylosuccinate lyase deficiency Uncertain:1
This sequence change replaces proline with arginine at codon 467 of the ADSL protein (p.Pro467Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with ADSL deficiency (PMID: 16839792, 20127976). ClinVar contains an entry for this variant (Variation ID: 381551). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ADSL function (PMID: 22180458). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at