chr12-53307698-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_015665.6(AAAS):c.1432C>T(p.Arg478*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,950 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 Pathogenic (★★).
Frequency
Consequence
NM_015665.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250206Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135474
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461784Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727184
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74352
ClinVar
Submissions by phenotype
Glucocorticoid deficiency with achalasia Pathogenic:6
ACMG criterias used: PS3, PS4, PM2. -
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not provided Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Arg478*) in the AAAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the AAAS protein. This variant is present in population databases (rs121918548, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with triple A syndrome (PMID: 11062474, 14646395, 29874194, 30381913). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate a damaging effect due to mislocalization of the ALADIN protein (Krumbholtz et al., 2006); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 11062474, 12008750, 16609705, 11914417, 14646395, 20499090, 30381913, 29874194, 31980526) -
Neurodevelopmental disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at