NM_152783.5:c.1258G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_152783.5(D2HGDH):c.1258G>A(p.Ala420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,604,926 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.441

Publications

9 publications found

Variant links:

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

D2HGDH Gene-Disease associations (from GenCC):

D-2-hydroxyglutaric aciduria 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
D-2-hydroxyglutaric aciduria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

D2HGDH links:

ENSG00000234793 (HGNC:):

ENSG00000234793 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_152783.5

BP4

Computational evidence support a benign effect (MetaRNN=0.015416682).

BP6

Variant 2-241755966-G-A is Benign according to our data. Variant chr2-241755966-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158409.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (355/152292) while in subpopulation NFE AF = 0.00337 (229/68012). AF 95% confidence interval is 0.00301. There are 0 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
D2HGDH	NM_152783.5 link	c.1258G>A	p.Ala420Thr	missense_variant	Exon 9 of 10	ENST00000321264.9	NP_689996.4	Q8N465-1B4E3K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9 link	c.1258G>A	p.Ala420Thr	missense_variant	Exon 9 of 10	1	NM_152783.5	ENSP00000315351.4		Q8N465-1

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

356

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00220

AC:

545

AN:

248050

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.000497

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00151

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00237

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00296

GnomAD4 exome

AF:

0.00302

AC:

4380

AN:

1452634

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2137

AN XY:

720814

show subpopulations

African (AFR)

AF:

0.000571

AC:

AN:

33270

American (AMR)

AF:

0.00146

AC:

AN:

44500

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

26040

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39398

South Asian (SAS)

AF:

0.00214

AC:

184

AN:

86094

European-Finnish (FIN)

AF:

0.00234

AC:

122

AN:

52230

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00345

AC:

3810

AN:

1105474

Other (OTH)

AF:

0.00224

AC:

134

AN:

59884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

271

541

812

1082

1353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00233

AC:

355

AN:

152292

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41564

American (AMR)

AF:

0.00320

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00337

AC:

229

AN:

68012

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.00236

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00218

AC:

264

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1

Uncertain:1Benign:2

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

D2HGDH: BP4, BS2 -

D2HGDH-related disorder

Benign:1

Oct 07, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

3.8

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.44

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.15

Sift

Benign

0.27

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0080

B;.

Vest4

0.16

MVP

0.74

MPC

0.37

ClinPred

0.0036

GERP RS

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.53

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over