Genetic Variant NM_013391.3:c.1936T>A (chr5-79028529-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013391.3(DMGDH):c.1936T>A(p.Ser646Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. S646P) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0810

Publications

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

DMGDH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08518523).

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.1936T>A	p.Ser646Thr	missense	Exon 12 of 16	NP_037523.2	Q9UI17-1
DMGDH	NR_104002.3		n.1521T>A		non_coding_transcript_exon	Exon 9 of 12
DMGDH	NR_104003.3		n.1073T>A		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.1936T>A	p.Ser646Thr	missense	Exon 12 of 16	ENSP00000255189.3	Q9UI17-1
DMGDH	ENST00000523732.1	TSL:1	c.1453T>A	p.Ser485Thr	missense	Exon 9 of 12	ENSP00000430972.1	Q8TCC6
DMGDH	ENST00000895914.1		c.1963T>A	p.Ser655Thr	missense	Exon 13 of 17	ENSP00000565973.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60394

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.052

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.68

M_CAP

Benign

0.015

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.1

PhyloP100

0.081

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.72

REVEL

Benign

0.12

Sift

Benign

0.55

Sift4G

Benign

0.35

Polyphen

0.0010

Vest4

0.065

MutPred

0.41

Loss of disorder (P = 0.0677)

MVP

0.60

MPC

0.13

ClinPred

0.064

GERP RS

2.1

Varity_R

0.12

gMVP

0.53

Mutation Taster

=87/13

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