5-79028529-A-G

Variant names:

Variant summary

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

The NM_013391.3(DMGDH):c.1936T>C(p.Ser646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,646 control chromosomes in the GnomAD database, including 69,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8780 hom., cov: 31)

Exomes 𝑓: 0.28 ( 61041 hom. )

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0810

Publications

48 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.9748678E-4).

BP6

Variant 5-79028529-A-G is Benign according to our data. Variant chr5-79028529-A-G is described in ClinVar as Benign. ClinVar VariationId is 380066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMGDH	NM_013391.3	MANE Select	c.1936T>C	p.Ser646Pro	missense	Exon 12 of 16	NP_037523.2
DMGDH	NR_104002.3		n.1521T>C		non_coding_transcript_exon	Exon 9 of 12
DMGDH	NR_104003.3		n.1073T>C		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.1936T>C	p.Ser646Pro	missense	Exon 12 of 16	ENSP00000255189.3
DMGDH	ENST00000523732.1	TSL:1	c.1453T>C	p.Ser485Pro	missense	Exon 9 of 12	ENSP00000430972.1
DMGDH	ENST00000517853.5	TSL:2	n.*698T>C		non_coding_transcript_exon	Exon 7 of 10	ENSP00000428995.1

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49564

AN:

151820

Hom.:

8771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.465

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.274

AC:

68746

AN:

251270

AF XY:

0.277

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.154

Gnomad ASJ exome

AF:

0.324

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.286

GnomAD4 exome

AF:

0.284

AC:

414880

AN:

1461706

Hom.:

61041

Cov.:

AF XY:

0.285

AC XY:

206944

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.466

AC:

15612

AN:

33474

American (AMR)

AF:

0.164

AC:

7318

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

8397

AN:

26130

East Asian (EAS)

AF:

0.145

AC:

5748

AN:

39688

South Asian (SAS)

AF:

0.300

AC:

25849

AN:

86258

European-Finnish (FIN)

AF:

0.269

AC:

14395

AN:

53414

Middle Eastern (MID)

AF:

0.324

AC:

1870

AN:

5768

European-Non Finnish (NFE)

AF:

0.287

AC:

318563

AN:

1111862

Other (OTH)

AF:

0.284

AC:

17128

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16593

33186

49780

66373

82966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10522

21044

31566

42088

52610

<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:

0.326

AC:

49603

AN:

151940

Hom.:

8780

Cov.:

AF XY:

0.324

AC XY:

24056

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.465

AC:

19260

AN:

41410

American (AMR)

AF:

0.229

AC:

3503

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1051

AN:

3466

East Asian (EAS)

AF:

0.147

AC:

760

AN:

5164

South Asian (SAS)

AF:

0.290

AC:

1394

AN:

4814

European-Finnish (FIN)

AF:

0.277

AC:

2924

AN:

10552

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.291

AC:

19801

AN:

67946

Other (OTH)

AF:

0.307

AC:

649

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1586

3172

4757

6343

7929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.303

Hom.:

23373

Bravo

AF:

0.325

TwinsUK

AF:

0.280

AC:

1039

ALSPAC

AF:

0.292

AC:

1124

ESP6500AA

AF:

0.455

AC:

2003

ESP6500EA

AF:

0.287

AC:

2466

ExAC

AF:

0.280

AC:

33968

Asia WGS

AF:

0.210

AC:

731

AN:

3478

EpiCase

AF:

0.301

EpiControl

AF:

0.304

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.55

MetaRNN

Benign

0.00030

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PhyloP100

0.081

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.15

Sift

Benign

0.17

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.040

MPC

0.18

ClinPred

0.0073

GERP RS

2.1

Varity_R

0.55

gMVP

0.76

Mutation Taster

=83/17

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over