rs202182817
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_001698.3(AUH):c.730G>A(p.Asp244Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000569 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00059 ( 1 hom. )
Consequence
AUH
NM_001698.3 missense
NM_001698.3 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 5.50
Genes affected
AUH (HGNC:890): (AU RNA binding methylglutaconyl-CoA hydratase) This gene encodes bifunctional mitochondrial protein that has both RNA-binding and hydratase activities. The encoded protein is a methylglutaconyl-CoA hydratase that catalyzes the hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA, a critical step in the leucine degradation pathway. This protein also binds AU-rich elements (AREs) found in the 3' UTRs of rapidly decaying mRNAs including c-fos, c-myc and granulocyte/ macrophage colony stimulating factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. This protein is localizes to the mitochondrial matrix and the inner mitochondrial membrane and may be involved in mitochondrial protein synthesis. Mutations in this gene are the cause of 3-methylglutaconic aciduria, type I. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001698.3
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.105192006).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AUH | NM_001698.3 | c.730G>A | p.Asp244Asn | missense_variant | 7/10 | ENST00000375731.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AUH | ENST00000375731.9 | c.730G>A | p.Asp244Asn | missense_variant | 7/10 | 1 | NM_001698.3 | P1 | |
AUH | ENST00000303617.5 | c.643G>A | p.Asp215Asn | missense_variant | 6/9 | 1 | |||
AUH | ENST00000473695.1 | n.2G>A | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000426 AC: 107AN: 251394Hom.: 1 AF XY: 0.000434 AC XY: 59AN XY: 135864
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GnomAD4 exome AF: 0.000587 AC: 858AN: 1461890Hom.: 1 Cov.: 31 AF XY: 0.000641 AC XY: 466AN XY: 727246
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GnomAD4 genome ? AF: 0.000401 AC: 61AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74454
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
3-methylglutaconic aciduria type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 244 of the AUH protein (p.Asp244Asn). This variant is present in population databases (rs202182817, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AUH-related conditions. ClinVar contains an entry for this variant (Variation ID: 214146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2022 | The c.730G>A (p.D244N) alteration is located in exon 7 (coding exon 7) of the AUH gene. This alteration results from a G to A substitution at nucleotide position 730, causing the aspartic acid (D) at amino acid position 244 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2018 | p.Asp244Asn (GAT>AAT): c.730 G>A in exon 7 of the AUH gene (NM_001698.2). The D244N missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative as a negatively charged Aspartic Acid residue is replaced by an uncharged Asparagine residue. This change occurs at a position in the AUH protein that is conserved in mammals. A missense mutation at a nearby position (A240V) has been reported in association with 3-methylglutaconic aciduria type 1. In-silico analyses are not consistent in their predictions of whether or not D244N is damaging to the AUH protein. Therefore, based on the currently available information, it is unclear whether D244N is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at