rs201921601

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_152783.5(D2HGDH):c.1184G>A(p.Arg395Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.23

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 links:

ENSG00000234793 (HGNC:):

ENSG00000234793 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052564234).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000276 (42/152344) while in subpopulation AFR AF = 0.000914 (38/41584). AF 95% confidence interval is 0.000684. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
D2HGDH	NM_152783.5 link	c.1184G>A	p.Arg395Gln	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.1184G>A	p.Arg395Gln	missense_variant	Exon 9 of 10	1	NM_152783.5	ENSP00000315351.4		Q8N465-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000717

AC:

AN:

251064

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1460832

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

AC:

AN:

33474

Gnomad4 AMR exome

AF:

0.000335

AC:

AN:

44718

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39668

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52838

Gnomad4 NFE exome

AF:

0.00000450

AC:

AN:

1111610

Gnomad4 Remaining exome

AF:

0.0000994

AC:

AN:

60364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome 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

GnomAD4 genome

AF:

0.000276

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000914

AC:

0.000913813

AN:

0.000913813

Gnomad4 AMR

AF:

0.000261

AC:

0.000261267

AN:

0.000261267

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000296

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1

Uncertain:3

Mar 12, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 29, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

2.0

M;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.18

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.71

P;.

Vest4

0.29

MVP

0.60

MPC

0.45

ClinPred

0.022

GERP RS

-0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.036

gMVP

0.55

Mutation Taster

=93/7

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

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