Genetic Variant DMGDH:c.2250+3618G>A (chr5-79020653-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_013391.3(DMGDH):c.2250+3618G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 965,396 control chromosomes in the GnomAD database, including 42,859 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 9118 hom., cov: 32)

Exomes 𝑓: 0.28 ( 33741 hom. )

Consequence

DMGDH
NM_013391.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Publications

35 publications found

Variant links:

Genes affected

DMGDH (HGNC:24475): (dimethylglycine dehydrogenase) This gene encodes an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine to form sarcosine. The enzyme is found as a monomer in the mitochondrial matrix, and uses flavin adenine dinucleotide and folate as cofactors. Mutation in this gene causes dimethylglycine dehydrogenase deficiency, characterized by a fishlike body odor, chronic muscle fatigue, and elevated levels of the muscle form of creatine kinase in serum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

DMGDH Gene-Disease associations (from GenCC):

dimethylglycine dehydrogenase deficiency
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

DMGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMGDH	NM_013391.3 link	c.2250+3618G>A		intron_variant	Intron 14 of 15	ENST00000255189.8	NP_037523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMGDH	ENST00000255189.8 link	c.2250+3618G>A		intron_variant	Intron 14 of 15	1	NM_013391.3	ENSP00000255189.3
DMGDH	ENST00000523732.1 link	c.*954G>A		downstream_gene_variant		1		ENSP00000430972.1

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

50294

AN:

151794

Hom.:

9108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.482

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.279

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.315

GnomAD4 exome

AF:

0.284

AC:

231187

AN:

813484

Hom.:

33741

Cov.:

AF XY:

0.284

AC XY:

106952

AN XY:

376370

show subpopulations

African (AFR)

AF:

0.489

AC:

7478

AN:

15282

American (AMR)

AF:

0.186

AC:

177

AN:

954

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1619

AN:

5024

East Asian (EAS)

AF:

0.154

AC:

545

AN:

3536

South Asian (SAS)

AF:

0.303

AC:

4852

AN:

15996

European-Finnish (FIN)

AF:

0.285

AC:

AN:

270

Middle Eastern (MID)

AF:

0.315

AC:

495

AN:

1570

European-Non Finnish (NFE)

AF:

0.280

AC:

208585

AN:

744174

Other (OTH)

AF:

0.276

AC:

7359

AN:

26678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

7039

14077

21116

28154

35193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9594

19188

28782

38376

47970

<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:

0.331

AC:

50335

AN:

151912

Hom.:

9118

Cov.:

AF XY:

0.328

AC XY:

24368

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.482

AC:

19939

AN:

41378

American (AMR)

AF:

0.232

AC:

3541

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1051

AN:

3468

East Asian (EAS)

AF:

0.149

AC:

768

AN:

5160

South Asian (SAS)

AF:

0.289

AC:

1395

AN:

4822

European-Finnish (FIN)

AF:

0.279

AC:

2938

AN:

10540

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.291

AC:

19787

AN:

67946

Other (OTH)

AF:

0.310

AC:

655

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1664

3327

4991

6654

8318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

490

980

1470

1960

2450

<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:

0.309

Hom.:

12680

Bravo

AF:

0.331

Asia WGS

AF:

0.210

AC:

731

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.8

(source)

DANN

Benign

0.58

PhyloP100

0.21

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over