rs1105273

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152783.5(D2HGDH):c.1082C>T(p.Ala361Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,613,572 control chromosomes in the GnomAD database, including 16,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A361A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2862 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13964 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.179

Publications

24 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057843626).

BP6

Variant 2-241751330-C-T is Benign according to our data. Variant chr2-241751330-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
D2HGDH	NM_152783.5	MANE Select	c.1082C>T	p.Ala361Val	missense	Exon 8 of 10	NP_689996.4
D2HGDH	NM_001287249.2		c.680C>T	p.Ala227Val	missense	Exon 7 of 9	NP_001274178.1
D2HGDH	NM_001352824.2		c.521C>T	p.Ala174Val	missense	Exon 8 of 10	NP_001339753.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.1082C>T	p.Ala361Val	missense	Exon 8 of 10	ENSP00000315351.4
D2HGDH	ENST00000436747.5	TSL:1	n.*1398C>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000400212.1
D2HGDH	ENST00000470343.5	TSL:1	n.563C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26909

AN:

152054

Hom.:

2858

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.266

Gnomad ASJ

AF:

0.0795

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.162

AC:

40568

AN:

250886

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.286

Gnomad AMR exome

AF:

0.320

Gnomad ASJ exome

AF:

0.0924

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.127

AC:

186154

AN:

1461400

Hom.:

13964

Cov.:

AF XY:

0.125

AC XY:

91025

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.278

AC:

9298

AN:

33478

American (AMR)

AF:

0.322

AC:

14397

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0932

AC:

2435

AN:

26136

East Asian (EAS)

AF:

0.238

AC:

9441

AN:

39700

South Asian (SAS)

AF:

0.114

AC:

9810

AN:

86248

European-Finnish (FIN)

AF:

0.144

AC:

7661

AN:

53036

Middle Eastern (MID)

AF:

0.104

AC:

602

AN:

5764

European-Non Finnish (NFE)

AF:

0.112

AC:

124132

AN:

1111962

Other (OTH)

AF:

0.139

AC:

8378

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

9734

19468

29201

38935

48669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4842

9684

14526

19368

24210

<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:

0.177

AC:

26943

AN:

152172

Hom.:

2862

Cov.:

AF XY:

0.179

AC XY:

13309

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.274

AC:

11383

AN:

41516

American (AMR)

AF:

0.266

AC:

4071

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0795

AC:

276

AN:

3470

East Asian (EAS)

AF:

0.214

AC:

1105

AN:

5164

South Asian (SAS)

AF:

0.118

AC:

570

AN:

4826

European-Finnish (FIN)

AF:

0.145

AC:

1534

AN:

10592

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.111

AC:

7533

AN:

67994

Other (OTH)

AF:

0.190

AC:

403

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1129

2259

3388

4518

5647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.133

Hom.:

3603

Bravo

AF:

0.194

TwinsUK

AF:

0.117

AC:

432

ALSPAC

AF:

0.109

AC:

422

ESP6500AA

AF:

0.265

AC:

1168

ESP6500EA

AF:

0.106

AC:

912

ExAC

AF:

0.155

AC:

18831

Asia WGS

AF:

0.198

AC:

686

AN:

3478

EpiCase

AF:

0.105

EpiControl

AF:

0.103

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

D-2-hydroxyglutaric aciduria 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.21

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.067

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

PhyloP100

0.18

PrimateAI

Benign

0.39

PROVEAN

Benign

0.59

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.067

MPC

0.38

ClinPred

0.0020

GERP RS

-7.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.60

Mutation Taster

=93/7

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over