rs121918548
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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.Arg478Ter) 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
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
AAAS
NM_015665.6 stop_gained
NM_015665.6 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.01
Genes affected
AAAS (HGNC:13666): (aladin WD repeat nucleoporin) The protein encoded by this gene is a member of the WD-repeat family of regulatory proteins and may be involved in normal development of the peripheral and central nervous system. The encoded protein is part of the nuclear pore complex and is anchored there by NDC1. Defects in this gene are a cause of achalasia-addisonianism-alacrima syndrome (AAAS), also called triple-A syndrome or Allgrove syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.127 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-53307698-G-A is Pathogenic according to our data. Variant chr12-53307698-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-53307698-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AAAS | NM_015665.6 | c.1432C>T | p.Arg478Ter | stop_gained | 16/16 | ENST00000209873.9 | |
AAAS | NM_001173466.2 | c.1333C>T | p.Arg445Ter | stop_gained | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AAAS | ENST00000209873.9 | c.1432C>T | p.Arg478Ter | stop_gained | 16/16 | 1 | NM_015665.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250206Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135474
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461784Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727184
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GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74352
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glucocorticoid deficiency with achalasia Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 12, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 29, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Jan 29, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 26, 2002 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2020 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Oct 07, 2021 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at