7-44624350-C-T

Position:

chr7-44624350-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.7C>T	p.His3Tyr	missense_variant	2/23	1	NM_002541.4	P3	Q02218-1

Frequencies

GnomAD3 genomes

AF:

0.00205

AC:

156

AN:

75944

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000872

AC XY:

AN XY:

112398

show subpopulations

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.:

Cov.:

AF XY:

0.00249

AC XY:

1278

AN XY:

512392

show subpopulations

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.:

Cov.:

AF XY:

0.00198

AC XY:

AN XY:

34368

show subpopulations

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.:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oxoglutaricaciduria

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

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

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D

M_CAP

Benign

0.0072

MetaRNN

Benign

0.021

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

.;L;.;L;.;.;.;L

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Uncertain

0.59

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over