7-44624423-G-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_002541.4(OGDH):c.80G>T(p.Arg27Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000279 in 1,609,912 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00035 ( 1 hom., cov: 30)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
OGDH
NM_002541.4 missense
NM_002541.4 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 4.86
Genes affected
OGDH (HGNC:8124): (oxoglutarate dehydrogenase) This gene encodes one subunit of the 2-oxoglutarate dehydrogenase complex. This complex catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and CO(2) during the Krebs cycle. The protein is located in the mitochondrial matrix and uses thiamine pyrophosphate as a cofactor. A congenital deficiency in 2-oxoglutarate dehydrogenase activity is believed to lead to hypotonia, metabolic acidosis, and hyperlactatemia. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), OGDH. . Gene score misZ 4.7595 (greater than the threshold 3.09). Trascript score misZ 5.6536 (greater than threshold 3.09). GenCC has associacion of gene with oxoglutaricaciduria.
BP4
Computational evidence support a benign effect (MetaRNN=0.0616588).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OGDH | NM_002541.4 | c.80G>T | p.Arg27Ile | missense_variant | 2/23 | ENST00000222673.6 | NP_002532.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OGDH | ENST00000222673.6 | c.80G>T | p.Arg27Ile | missense_variant | 2/23 | 1 | NM_002541.4 | ENSP00000222673.5 |
Frequencies
GnomAD3 genomes AF: 0.000351 AC: 52AN: 148246Hom.: 1 Cov.: 30
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GnomAD3 exomes AF: 0.000302 AC: 76AN: 251476Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135912
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GnomAD4 exome AF: 0.000272 AC: 397AN: 1461666Hom.: 0 Cov.: 35 AF XY: 0.000253 AC XY: 184AN XY: 727130
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GnomAD4 genome AF: 0.000351 AC: 52AN: 148246Hom.: 1 Cov.: 30 AF XY: 0.000404 AC XY: 29AN XY: 71710
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Oxoglutaricaciduria Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 23, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with OGDH-related conditions. This variant is present in population databases (rs145219519, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 27 of the OGDH protein (p.Arg27Ile). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.;T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;L;.;.;.;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;.;N
REVEL
Benign
Sift
Uncertain
D;D;T;T;D;T;.;T
Sift4G
Uncertain
T;D;T;T;T;T;T;T
Polyphen
B;.;B;.;.;.;.;B
Vest4
MVP
MPC
0.56
ClinPred
T
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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