rs543840147
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.271dupA(p.Arg91LysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R91R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00098 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0010 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 frameshift
NM_015506.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.08
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-45507544-T-TA is Pathogenic according to our data. Variant chr1-45507544-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 1421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MMACHC | NM_015506.3 | c.271dupA | p.Arg91LysfsTer14 | frameshift_variant | Exon 2 of 4 | ENST00000401061.9 | NP_056321.2 | |
| MMACHC | NM_001330540.2 | c.100dupA | p.Arg34LysfsTer14 | frameshift_variant | Exon 2 of 4 | NP_001317469.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MMACHC | ENST00000401061.9 | c.271dupA | p.Arg91LysfsTer14 | frameshift_variant | Exon 2 of 4 | 2 | NM_015506.3 | ENSP00000383840.4 | ||
| MMACHC | ENST00000616135.1 | c.100dupA | p.Arg34LysfsTer14 | frameshift_variant | Exon 2 of 5 | 2 | ENSP00000478859.1 |
Frequencies
GnomAD3 genomes 0.000986 AC: 150AN: 152168Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00116 AC: 290AN: 249456Hom.: 0 AF XY: 0.00126 AC XY: 170AN XY: 135346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:47Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:26
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 11, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 strong - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.270_271insA;p.(Arg91Lysfs*14) is a null frameshift variant (NMD) in the MMACHC gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1421; PMID: 16311595; PMID: 19760748; PMID: 20631720; PMID: 24599607; PMID: 25894566) - PS4. The variant is present at low allele frequencies population databases (rs398124292 – gnomAD 0.00008037%; ABraOM 0.003843 frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 4). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (314 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants also predicted to result in NMD, have very strong previous evidence for pathogenicity in patients with Methylmalonic acidemia (Decipher, ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in many unrelated individuals with Methylmalonic acidemia (LOVD, ClinVar, PMID: 31279840). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Elsea Laboratory, Baylor College of Medicine | Apr 01, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 15, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 05, 2020 | - - |
| Pathogenic, no assertion criteria provided | research | Neurology Department, Peking University First Hospital | Apr 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 20, 2021 | This variant was identified as compound heterozygous with NM_015506.3:c.658_660del._x000D_ Criteria applied: PVS1, PM3_VSTR, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 12, 2016 | Variant summary: The MMACHC c.271dupA (p.Arg91Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 132/120196 control chromosomes at a frequency of 0.0010982, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant is a well known common disease variant and has been reported in numerous affected individuals in the literature, including individuals carrying the variant in the homozygous and compound heterozygous state (Lerner-Ellis_2006). Supporting the pathogenicity of this variant, incorporation of labelled methyltetrahydrofolate and propionate into cellular macromolecules was significantly affected in patients with homozygous or compound heterozygous c.271dupA (Lerner-Ellis_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Feb 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is classified as pathogenic in the context of cblC type methylmalonic aciduria and homocystinuria and may be associated with the early onset form of disease. Sources cited for classification include the following: PMID 19370762. Classification of NM_015506.2(MMACHC):c.271dupA(R91Kfs*14) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 13, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2025 | This sequence change creates a premature translational stop signal (p.Arg91Lysfs*14) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs543840147, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with early onset cobalamin C deficiency (PMID: 16311595, 19760748, 20631720, 24599607, 25894566). ClinVar contains an entry for this variant (Variation ID: 1421). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 08, 2013 | The Arg91LysfsX14 variant in MMACHC has been identified in homozygosity in 81 individuals and in compound heterozygosity in 86 individuals with methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis 2006, Richard 2009, Liu 2010). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 91 and lead to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 25, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris | Jan 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 10, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Apr 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed frameshift variant c.271dup(p.Arg91LysfsTer14) in MMACHC gene has been reported previously in homozygous and compound heterozygous state in multiple individuals with cobalamin C disease (Wang C, et al., 2019, Guéant JL, et al., 2018). Experimental evidence has demonstrated a significant reduction in transcript levels in the presence of this variant (Lerner-Ellis JP, et al., 2009). The c.271dup variant is reported with 0.1% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance/Pathogenic (multiple submissions).This variant causes a frameshift starting with codon Arginine at 91, changes this aminoacid to Lysine residue, and creates a premature stop codon at position 14 of the new reading frame, denoted p.Arg91LysfsTer14. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.112%). This variant was 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001421 / PMID: 16311595). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 13, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 03, 2020 | This duplication causes a shift in the reading frame and is expected to result in the loss of a functional protein. Experimental evidence has demonstrated a significant reduction in transcript levels in the presence of this variant (PMID: 19370762). This variant has been identified homozygous and compound heterozygous in multiple individuals with clinical features associated with this gene, and has been reported as a common disease causing variant (PMID: 16311595, 19760748, 20631720, 24599607). The frequency of this variant in the general population is consistent with pathogenicity for a recessive disorder (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 28, 2021 | PVS1, PS3, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 27, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 26, 2023 | PM3_very_strong, PS3, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24599607, 19760748, 25687216, 32164588, 31681265, 24210589, 20631720, 23954310, 23837176, 21228398, 16311595, 25894566, 26979128, 27014578, 29302025, 26990548, 30712249, 29294253, 28835862, 31137025, 28481040, 27252276, 31497484, 31574870, 32071835, 31503356, 30157807, 31998365, 31980526, 31589614, 32943488, 33587123) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2024 | MMACHC: PM3:Very Strong, PVS1, PM2:Supporting, PP4, PS3:Supporting - |
See cases Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 06, 2022 | ACMG classification criteria: PVS1, PS4, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Sep 25, 2024 | ACMG categories: PVS1,PS3,PS4,PM3 - |
Disorders of Intracellular Cobalamin Metabolism Pathogenic:1Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 26, 2017 | The MMACHC c.271dupA (p.Arg91LysfsTer14) variant, also referred to as c.270_271insA, results in a frameshift variant and is predicted to result in premature termination of the protein. The p.Arg91LysfsTer14 variant is well described in the literature and is reported as the most common pathogenic variant in the MMACHC gene accounting for approximately 40% of disease alleles (Manoli et al. 2016). The variant has been reported in at least 12 studies in which it was found in over 270 individuals with disorders of intracellular cobalamin metabolism, including at least 127 in a homozygous state and 143 in a compound heterozygous state (Lerner-Ellis et al. 2006; Morel et al. 2006; Heil et al. 2007; Nogueira et al. 2008; Lerner-Ellis et al. 2009; Perez et al. 2010; Frattini et al. 2010; Tsai et al. 2011; Komhoff et al. 2103; Gizicki et al. 2014; Fischer et al. 2014; Collison et al. 2015). The variant was absent from 105 controls and is reported at a frequency of 0.00173 in the European American population of the Exome Sequencing Project. Individuals who carry the p.Arg91LysfsTer14 variant in a homozygous state tend to have an earlier age of onset of the condition while the age of onset of disease when carried in the compound heterozygous state varies depending on the second variant (Morel et al. 2006). Functional studies in patient fibroblasts demonstrated that the p.Arg91LysfsTer variant results in significantly lower levels of transcript compared to wild type. Based on the potential impact of frameshift variants and the supporting evidence from the literature, the p.Arg91LysfsTer14 variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| not provided, no classification provided | literature only | GeneReviews | - | Accounts for approximately 30%-50% of disease alleles in individuals of European ancestry. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 05, 2016 | - - |
Methylmalonic aciduria and homocystinuria Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PS3,PM3,PM2,PP4 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2021 | The c.271dupA (p.R91Kfs*14) alteration, located in exon 2 (coding exon 2) of the MMACHC gene, consists of a duplication of A at position 271, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the MMACHC c.271dupA alteration was observed in 0.11% (314/280836) of total alleles studied, with a frequency of 0.28% (29/10356) in the Ashkenazi Jewish subpopulation. This mutation has been reported in the homozygous and compound heterozygous states in multiple unrelated patients with methylmalonic aciduria and homocystinuria, cblC type. It is the most frequently identified MMACHC mutation accounting for 30-50% of alleles and is typically associated with infantile onset disease (Lerner-Ellis, 2006; Richard, 2009; Fischer, 2014). Based on the available evidence, this alteration is classified as pathogenic. - |
MMACHC-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The MMACHC c.271dupA variant is predicted to result in a frameshift and premature protein termination (p.Arg91Lysfs*14). This variant is one of the most commonly reported pathogenic variants causative for methylmalonic acidemia and homocystinuria, cblC type (Lerner-Ellis et al. 2006. PubMed ID: 16311595; Richard et al. 2009. PubMed ID: 19760748). It has been interpreted as pathogenic by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/1421/). This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Numerous other premature protein termination variants in MMACHC have been reported to be disease-causing (Human Gene Mutation Database). This variant is interpreted as pathogenic. - |
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE, DIGENIC Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Atypical hemolytic-uremic syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | May 09, 2019 | This individual is heterozygous for a pathogenic variant c.271dup in the MMACHC gene. This frameshifting variant is predicted to create a premature stop codon p.(Arg91Lysfs*14) and may result in a null allele due to nonsense-mediated mRNA decay. This variant is one of the most common variants associated with cblC type methylmalonic aciduria and homocystinuria (Lerner-Ellis et al 2006 Nat Genet 38:93-100). This variant is considered to be pathogenic according to the ACMG guidelines. - |
Methylmalonic acidemia with homocystinuria cblC Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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