rs747431164
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001605.3(AARS1):c.333+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
AARS1
NM_001605.3 splice_donor_region, intron
NM_001605.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0003523
2
Clinical Significance
Conservation
PhyloP100: 2.13
Genes affected
AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS1 | NM_001605.3 | c.333+3A>G | splice_donor_region_variant, intron_variant | ENST00000261772.13 | |||
AARS1 | XM_047433666.1 | c.333+3A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS1 | ENST00000261772.13 | c.333+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_001605.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251470Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135910
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727244
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2021 | Unlikely to be causative of Charcot-Marie-Tooth disease (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change falls in intron 3 of the AARS gene. It does not directly change the encoded amino acid sequence of the AARS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs747431164, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with AARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1060939). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at