16-70252896-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001605.3(AARS1):āc.2732A>Gā(p.Asn911Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001605.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS1 | NM_001605.3 | c.2732A>G | p.Asn911Ser | missense_variant | 21/21 | ENST00000261772.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS1 | ENST00000261772.13 | c.2732A>G | p.Asn911Ser | missense_variant | 21/21 | 1 | NM_001605.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152062Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000104 AC: 26AN: 250788Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135584
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461860Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52AN XY: 727240
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152062Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74250
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Reported previously as a variant of uncertain significance in a patient with a suspected diagnosis of Charcot-Marie-Tooth disease; however, clinical and segregation information was not provided (Volodarsky et al., 2021); Reported in a patient with Sotos syndrome, intellectual disability, progressive sensory and motor axonal neuropathy, and leg spasticity in the published literature who also had variants in 5 other genes that may have been responsible for the phenotype (Gonzaga-Jauregui et al., 2015); This variant is associated with the following publications: (PMID: 25817015, 27309375, 32376792, 26257172) - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2021 | The p.N911S variant (also known as c.2732A>G), located in coding exon 20 of the AARS gene, results from an A to G substitution at nucleotide position 2732. The asparagine at codon 911 is replaced by serine, an amino acid with highly similar properties. This variant was detected in an individual with Charcot-Marie-Tooth disease, who also had variants in other genes associated with neuropathy (Gonzaga-Jauregui C et al. Cell Rep, 2015 Aug;12:1169-83). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie-Tooth disease, axonal, type 2N (CMT2N); however, its contribution to the development of AARS-related early infantile epileptic encephalopathy (EIEE) is uncertain. - |
AARS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 08, 2022 | The AARS1 c.2732A>G variant is predicted to result in the amino acid substitution p.Asn911Ser. Asn911Ser. This variant was reported as a variant of uncertain significance in an individual with Charcot-Marie-Tooth disease; however, pathogenicity was not established (Supplementary Table 2, Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.089% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-70286799-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | - - |
Charcot-Marie-Tooth disease axonal type 2N Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at