rs121908331

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3PP5_Very_StrongBP4

The NM_013391.3(DMGDH):c.326A>G(p.His109Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,612,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006581895: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:18937046)."" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.91

Publications

13 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

DMGDH links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_013391.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV006581895: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18937046)."; SCV000617314: Published functional studies demonstrate a damaging effect with inactivation of the dimethylglycine dehydrogenase enzyme (Binzak et al, 2001; McAndrew et al., 2008; Augustin et al., 2016)

PP5

Variant 5-79055859-T-C is Pathogenic according to our data. Variant chr5-79055859-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.030004412). . Strength limited to SUPPORTING due to the PP5.

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	UniProt
DMGDH	NM_013391.3	MANE Select	c.326A>G	p.His109Arg	missense	Exon 3 of 16	NP_037523.2	Q9UI17-1
DMGDH	NR_104002.3		n.330+7754A>G		intron	N/A
DMGDH	NR_104003.3		n.330+7754A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.326A>G	p.His109Arg	missense	Exon 3 of 16	ENSP00000255189.3	Q9UI17-1
DMGDH	ENST00000895914.1		c.353A>G	p.His118Arg	missense	Exon 4 of 17	ENSP00000565973.1
DMGDH	ENST00000895909.1		c.233A>G	p.His78Arg	missense	Exon 3 of 16	ENSP00000565968.1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

210

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00475

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000394

AC:

AN:

251002

AF XY:

0.000332

show subpopulations

Gnomad AFR exome

AF:

0.00451

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000196

AC:

286

AN:

1460382

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

726674

show subpopulations

African (AFR)

AF:

0.00434

AC:

145

AN:

33446

American (AMR)

AF:

0.000537

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000693

AC:

AN:

1110738

Other (OTH)

AF:

0.000580

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00138

AC:

210

AN:

152382

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00474

AC:

197

AN:

41588

American (AMR)

AF:

0.000457

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68042

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000469

Hom.:

Bravo

AF:

0.00151

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dimethylglycine dehydrogenase deficiency (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

0.089

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.033

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.5

PhyloP100

7.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.66

Sift

Benign

0.095

Sift4G

Benign

0.19

Varity_R

0.86

gMVP

0.92

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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