Genetic Variant OGDH:p.Gly86Val (chr7-44645361-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002541.4(OGDH):c.257G>T(p.Gly86Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

OGDH
NM_002541.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Publications

0 publications found

Variant links:

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]

OGDH Gene-Disease associations (from GenCC):

oxoglutaricaciduria
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

OGDH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002541.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OGDH	NM_002541.4	MANE Select	c.257G>T	p.Gly86Val	missense	Exon 3 of 23	NP_002532.2	Q02218-1
OGDH	NM_001439007.1		c.257G>T	p.Gly86Val	missense	Exon 3 of 24	NP_001425936.1
OGDH	NM_001363523.2		c.257G>T	p.Gly86Val	missense	Exon 3 of 24	NP_001350452.1	E9PDF2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OGDH	ENST00000222673.6	TSL:1 MANE Select	c.257G>T	p.Gly86Val	missense	Exon 3 of 23	ENSP00000222673.5	Q02218-1
OGDH	ENST00000443864.6	TSL:1	c.257G>T	p.Gly86Val	missense	Exon 3 of 9	ENSP00000388084.2	Q02218-3
OGDH	ENST00000962345.1		c.257G>T	p.Gly86Val	missense	Exon 3 of 25	ENSP00000632404.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.8

PhyloP100

9.6

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.59

Sift

Benign

0.041

Sift4G

Uncertain

0.018

Polyphen

0.92

Vest4

0.87

MutPred

0.38

Loss of disorder (P = 0.0235)

MVP

0.58

MPC

1.2

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.76

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over