NM_013391.3:c.835T>C

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.835T>C(p.Ser279Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,386 control chromosomes in the GnomAD database, including 235,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 24034 hom., cov: 33)

Exomes 𝑓: 0.54 ( 211515 hom. )

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.96

Publications

40 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=1.2679009E-6).

BP6

Variant 5-79044463-A-G is Benign according to our data. Variant chr5-79044463-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 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.835T>C	p.Ser279Pro	missense	Exon 6 of 16	NP_037523.2
DMGDH	NR_104002.3		n.420T>C		non_coding_transcript_exon	Exon 3 of 12
DMGDH	NR_104003.3		n.331-11055T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.835T>C	p.Ser279Pro	missense	Exon 6 of 16	ENSP00000255189.3
DMGDH	ENST00000523732.1	TSL:1	c.352T>C	p.Ser118Pro	missense	Exon 3 of 12	ENSP00000430972.1
DMGDH	ENST00000518477.5	TSL:2	n.*69T>C		non_coding_transcript_exon	Exon 3 of 12	ENSP00000427834.1

Frequencies

GnomAD3 genomes

AF:

0.559

AC:

84951

AN:

151970

Hom.:

24003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.598

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.579

Gnomad ASJ

AF:

0.486

Gnomad EAS

AF:

0.780

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.532

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.560

GnomAD2 exomes

AF:

0.559

AC:

140606

AN:

251334

AF XY:

0.558

show subpopulations

Gnomad AFR exome

AF:

0.603

Gnomad AMR exome

AF:

0.581

Gnomad ASJ exome

AF:

0.475

Gnomad EAS exome

AF:

0.781

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.524

Gnomad OTH exome

AF:

0.530

GnomAD4 exome

AF:

0.535

AC:

782218

AN:

1461298

Hom.:

211515

Cov.:

AF XY:

0.536

AC XY:

389412

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.593

AC:

19852

AN:

33464

American (AMR)

AF:

0.574

AC:

25657

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.476

AC:

12441

AN:

26132

East Asian (EAS)

AF:

0.765

AC:

30368

AN:

39698

South Asian (SAS)

AF:

0.569

AC:

49078

AN:

86246

European-Finnish (FIN)

AF:

0.528

AC:

28209

AN:

53398

Middle Eastern (MID)

AF:

0.548

AC:

3158

AN:

5768

European-Non Finnish (NFE)

AF:

0.522

AC:

580034

AN:

1111508

Other (OTH)

AF:

0.554

AC:

33421

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

21409

42818

64228

85637

107046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16798

33596

50394

67192

83990

<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:

0.559

AC:

85033

AN:

152088

Hom.:

24034

Cov.:

AF XY:

0.559

AC XY:

41549

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.598

AC:

24799

AN:

41478

American (AMR)

AF:

0.579

AC:

8858

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.486

AC:

1686

AN:

3468

East Asian (EAS)

AF:

0.779

AC:

4030

AN:

5172

South Asian (SAS)

AF:

0.570

AC:

2743

AN:

4816

European-Finnish (FIN)

AF:

0.532

AC:

5623

AN:

10562

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.519

AC:

35299

AN:

67988

Other (OTH)

AF:

0.563

AC:

1187

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1921

3842

5763

7684

9605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.536

Hom.:

59160

Bravo

AF:

0.566

TwinsUK

AF:

0.529

AC:

1961

ALSPAC

AF:

0.514

AC:

1982

ESP6500AA

AF:

0.601

AC:

2648

ESP6500EA

AF:

0.526

AC:

4526

ExAC

AF:

0.561

AC:

68148

Asia WGS

AF:

0.696

AC:

2421

AN:

3478

EpiCase

AF:

0.522

EpiControl

AF:

0.523

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.019

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.7

PhyloP100

8.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

5.9

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.054

MPC

0.18

ClinPred

0.012

GERP RS

5.3

Varity_R

0.16

gMVP

0.55

Mutation Taster

=66/34

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over