Genetic Variant NM_013391.3:c.2122G>T (chr5-79026492-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013391.3(DMGDH):c.2122G>T(p.Asp708Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D708N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.00

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2122G>T	p.Asp708Tyr	missense	Exon 13 of 16	NP_037523.2
DMGDH	NR_104002.3		n.1707G>T		non_coding_transcript_exon	Exon 10 of 12
DMGDH	NR_104003.3		n.1259G>T		non_coding_transcript_exon	Exon 8 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.2122G>T	p.Asp708Tyr	missense	Exon 13 of 16	ENSP00000255189.3
DMGDH	ENST00000523732.1	TSL:1	c.1639G>T	p.Asp547Tyr	missense	Exon 10 of 12	ENSP00000430972.1
DMGDH	ENST00000517853.5	TSL:2	n.*884G>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000428995.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251408

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.63

MetaSVM

Uncertain

-0.048

MutationAssessor

Uncertain

2.5

PhyloP100

6.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.43

Sift

Benign

0.037

Sift4G

Benign

0.070

Polyphen

0.59

Vest4

0.80

MutPred

0.47

Loss of disorder (P = 0.0416)

MVP

0.83

MPC

0.61

ClinPred

0.98

GERP RS

5.3

Varity_R

0.71

gMVP

0.91

Mutation Taster

=58/42

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over