rs138081804
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4BP6BS1BS2
The NM_001605.3(AARS1):c.2185C>T(p.Arg729Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729Q) has been classified as Likely benign.
Frequency
Consequence
NM_001605.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS1 | NM_001605.3 | c.2185C>T | p.Arg729Trp | missense_variant | 16/21 | ENST00000261772.13 | |
AARS1 | XM_047433666.1 | c.2000C>T | p.Ala667Val | missense_variant | 15/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS1 | ENST00000261772.13 | c.2185C>T | p.Arg729Trp | missense_variant | 16/21 | 1 | NM_001605.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000710 AC: 108AN: 152196Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000647 AC: 161AN: 249026Hom.: 1 AF XY: 0.000601 AC XY: 81AN XY: 134678
GnomAD4 exome AF: 0.00130 AC: 1905AN: 1460850Hom.: 3 Cov.: 31 AF XY: 0.00120 AC XY: 871AN XY: 726666
GnomAD4 genome ? AF: 0.000702 AC: 107AN: 152314Hom.: 0 Cov.: 31 AF XY: 0.000645 AC XY: 48AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:5
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 28, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2023 | Reported in individuals with Charcot-Marie-Tooth disease; however it was also identified in 2/1090 normal control chromosomes (PMID: 22009580); Reported as a variant of uncertain significance in an individual with CMT2; the patient was also found to have a variant in another gene and it was unclear if either variant was causative for the patient's phenotype (PMID: 26752306); Reported in an individual with axonal neuropathy; the R729W variant does not segregate with disease in the family as it was observed in both affected and unaffected family members and was absent in affected family members, and the patient was also found to have a variant in another gene that appears to segregate with disease in the family (PMID: 30642740); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32376792, 25817015, Elshiekh2020[article], 22009580, 26752306, 30642740) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 10, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | literature only | Northcott Neuroscience Laboratory, ANZAC Research Institute | - | - - |
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 | Oct 31, 2023 | Unlikely to be causative of AARS-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Charcot-Marie-Tooth disease axonal type 2N Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at