chr9-32408593-C-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002197.3(ACO1):āc.346C>Gā(p.Pro116Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,862 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 (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000075 ( 0 hom. )
Consequence
ACO1
NM_002197.3 missense
NM_002197.3 missense
Scores
8
6
3
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
ACO1 (HGNC:117): (aconitase 1) The protein encoded by this gene is a bifunctional, cytosolic protein that functions as an essential enzyme in the TCA cycle and interacts with mRNA to control the levels of iron inside cells. When cellular iron levels are high, this protein binds to a 4Fe-4S cluster and functions as an aconitase. Aconitases are iron-sulfur proteins that function to catalyze the conversion of citrate to isocitrate. When cellular iron levels are low, the protein binds to iron-responsive elements (IREs), which are stem-loop structures found in the 5' UTR of ferritin mRNA, and in the 3' UTR of transferrin receptor mRNA. When the protein binds to IRE, it results in repression of translation of ferritin mRNA, and inhibition of degradation of the otherwise rapidly degraded transferrin receptor mRNA. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alternative splicing results in multiple transcript variants [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACO1 | NM_002197.3 | c.346C>G | p.Pro116Ala | missense_variant | 4/21 | ENST00000309951.8 | |
ACO1 | NM_001278352.2 | c.346C>G | p.Pro116Ala | missense_variant | 5/22 | ||
ACO1 | NM_001362840.2 | c.346C>G | p.Pro116Ala | missense_variant | 5/22 | ||
ACO1 | XM_047423430.1 | c.370C>G | p.Pro124Ala | missense_variant | 4/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACO1 | ENST00000309951.8 | c.346C>G | p.Pro116Ala | missense_variant | 4/21 | 1 | NM_002197.3 | P1 | |
ACO1 | ENST00000379923.5 | c.346C>G | p.Pro116Ala | missense_variant | 5/22 | 5 | P1 | ||
ACO1 | ENST00000541043.5 | c.346C>G | p.Pro116Ala | missense_variant | 5/22 | 5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135890
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727234
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2024 | The c.346C>G (p.P116A) alteration is located in exon 4 (coding exon 3) of the ACO1 gene. This alteration results from a C to G substitution at nucleotide position 346, causing the proline (P) at amino acid position 116 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;H;H
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP
MPC
0.82
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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