rs371595630
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_001605.3(AARS1):c.1811A>G(p.Asn604Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,016 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N604K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001605.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS1 | NM_001605.3 | c.1811A>G | p.Asn604Ser | missense_variant | 14/21 | ENST00000261772.13 | |
AARS1 | XM_047433666.1 | c.1811A>G | p.Asn604Ser | missense_variant | 14/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS1 | ENST00000261772.13 | c.1811A>G | p.Asn604Ser | missense_variant | 14/21 | 1 | NM_001605.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000175 AC: 44AN: 251462Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135910
GnomAD4 exome AF: 0.000163 AC: 238AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 123AN XY: 727234
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74320
ClinVar
Submissions by phenotype
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 | Dec 08, 2020 | The p.N604S variant (also known as c.1811A>G), located in coding exon 13 of the AARS gene, results from an A to G substitution at nucleotide position 1811. The asparagine at codon 604 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 604 of the AARS protein (p.Asn604Ser). This variant is present in population databases (rs371595630, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 543167). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AARS protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at