7-44624350-C-T

Position:

• chr7-44624350-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_002541.4(OGDH):​c.7C>T​(p.His3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,130,772 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: OGDH NM_002541.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• 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=0.02072218).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OGDH	NM_002541.4	c.7C>T	p.His3Tyr	missense_variant	2/23	ENST00000222673.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OGDH	ENST00000222673.6	c.7C>T	p.His3Tyr	missense_variant	2/23	1	NM_002541.4	P3

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 156 AN: 75944 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000411

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00216

GnomAD3 exomes AF: 0.000888 AC: 182 AN: 204926 Hom.: 1 AF XY: 0.000872 AC XY: 98 AN XY: 112398

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000462

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00244 AC: 2573 AN: 1054798 Hom.: 5 Cov.: 36 AF XY: 0.00249 AC XY: 1278 AN XY: 512392

Gnomad4 AFR exome AF: 0.000205

Gnomad4 AMR exome AF: 0.000721

Gnomad4 ASJ exome AF: 0.000194

Gnomad4 EAS exome AF: 0.000195

Gnomad4 SAS exome AF: 0.000277

Gnomad4 FIN exome AF: 0.000161

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.00205 AC: 156 AN: 75974 Hom.: 0 Cov.: 18 AF XY: 0.00198 AC XY: 68 AN XY: 34368

Gnomad4 AFR AF: 0.000548

Gnomad4 AMR AF: 0.00162

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000413

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00214

Alfa AF: 0.00181 Hom.: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oxoglutaricaciduria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 3 of the OGDH protein (p.His3Tyr). This variant is present in population databases (rs113587743, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OGDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1355335). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;.;.;.;T;T;T;T
Eigen	Benign	0.085
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.021	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;.;N
REVEL	Benign	0.089
Sift	Uncertain	0.0070	D;D;D;D;D;D;.;D
Sift4G	Benign	0.13	T;D;D;D;T;D;D;D
Polyphen		0.19	B;.;B;.;.;.;.;P
Vest4		0.45
MVP		0.26
MPC		0.40
ClinPred		0.051	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs113587743; hg19: chr7-44663949; COSMIC: COSV56050014;