rs746488412
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting
The NM_024666.5(AAGAB):c.481C>T(p.Arg161Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,644 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024666.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AAGAB | NM_024666.5 | c.481C>T | p.Arg161Ter | stop_gained | 5/10 | ENST00000261880.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AAGAB | ENST00000261880.10 | c.481C>T | p.Arg161Ter | stop_gained | 5/10 | 1 | NM_024666.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249538Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135378
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459644Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4AN XY: 726174
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Palmoplantar keratoderma, punctate type 1A Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). The variant has been reported to be associated with AAGAB related disorder (ClinVar ID: VCV000039732, PMID:23000146). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | This variant is present in population databases (rs746488412, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg161*) in the AAGAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAGAB are known to be pathogenic (PMID: 23000146, 23064416, 23563198, 23633024, 24390136). This premature translational stop signal has been observed in individual(s) with punctate palmoplantar keratoderma, type Buschke-Fischer-Brauer (PMID: 23000146). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39732). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at