NM_002541.4:c.29A>G

Variant names:

• chr7-44624372-A-G
• rs746503389
• NM_002541.4:c.29A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002541.4(OGDH):​c.29A>G​(p.Lys10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 29)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: OGDH NM_002541.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05783698).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OGDH	NM_002541.4	MANE Select	c.29A>G	p.Lys10Arg	missense	Exon 2 of 23	NP_002532.2	Q02218-1
	OGDH	NM_001439007.1		c.29A>G	p.Lys10Arg	missense	Exon 2 of 24	NP_001425936.1
	OGDH	NM_001363523.2		c.29A>G	p.Lys10Arg	missense	Exon 2 of 24	NP_001350452.1	E9PDF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OGDH	ENST00000222673.6	TSL:1 MANE Select	c.29A>G	p.Lys10Arg	missense	Exon 2 of 23	ENSP00000222673.5	Q02218-1
	OGDH	ENST00000443864.6	TSL:1	c.29A>G	p.Lys10Arg	missense	Exon 2 of 9	ENSP00000388084.2	Q02218-3
	OGDH	ENST00000962345.1		c.29A>G	p.Lys10Arg	missense	Exon 2 of 25	ENSP00000632404.1

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146520 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000446

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251376 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461680 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146520 Hom.: 1 Cov.: 29 AF XY: 0.0000423 AC XY: 3 AN XY: 70890

African (AFR) AF: 0.00 AC: 0 AN: 39198

American (AMR) AF: 0.00 AC: 0 AN: 14278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5028

South Asian (SAS) AF: 0.00 AC: 0 AN: 4538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000446 AC: 3 AN: 67216

Other (OTH) AF: 0.00 AC: 0 AN: 1982

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.10
Sift	Benign	0.28	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.33		Gain of methylation at K10 (P = 0.0075)
MVP		0.41
MPC		0.25
ClinPred		0.19	T
GERP RS		3.6
Varity_R		0.098
gMVP		0.36
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs746503389; hg19: chr7-44663971;