7-44624350-C-A

Variant names:

• chr7-44624350-C-A
• rs113587743
• NM_002541.4:c.7C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002541.4(OGDH):​c.7C>A​(p.His3Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000177 in 1,130,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 18)
  • Exomes 𝑓: 9.5e-7 (0 hom.)
• Consequence: OGDH NM_002541.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15208703).

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.7C>A	p.His3Asn	missense	Exon 2 of 23	NP_002532.2	Q02218-1
	OGDH	NM_001439007.1		c.7C>A	p.His3Asn	missense	Exon 2 of 24	NP_001425936.1
	OGDH	NM_001363523.2		c.7C>A	p.His3Asn	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.7C>A	p.His3Asn	missense	Exon 2 of 23	ENSP00000222673.5	Q02218-1
	OGDH	ENST00000443864.6	TSL:1	c.7C>A	p.His3Asn	missense	Exon 2 of 9	ENSP00000388084.2	Q02218-3
	OGDH	ENST00000962345.1		c.7C>A	p.His3Asn	missense	Exon 2 of 25	ENSP00000632404.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 1 AN: 75946 Hom.: 0 Cov.: 18

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: 0.0000252

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.48e-7 AC: 1 AN: 1054908 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 512458

African (AFR) AF: 0.00 AC: 0 AN: 24414

American (AMR) AF: 0.00 AC: 0 AN: 29136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15440

East Asian (EAS) AF: 0.00 AC: 0 AN: 20532

South Asian (SAS) AF: 0.00 AC: 0 AN: 50582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2856

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842254

Other (OTH) AF: 0.00 AC: 0 AN: 38554

GnomAD4 genome AF: 0.0000132 AC: 1 AN: 75946 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 34332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20030

American (AMR) AF: 0.00 AC: 0 AN: 4938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2208

East Asian (EAS) AF: 0.00 AC: 0 AN: 2570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 74

European-Non Finnish (NFE) AF: 0.0000252 AC: 1 AN: 39716

Other (OTH) AF: 0.00 AC: 0 AN: 928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.079
Sift	Benign	0.19	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.37		Gain of disorder (P = 0.0735)
MVP		0.43
MPC		0.34
ClinPred		0.51	D
GERP RS		3.8
Varity_R		0.18
gMVP		0.40
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs113587743; hg19: chr7-44663949;