Variant chr5-79024308-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_013391.3(DMGDH):c.2213T>G(p.Leu738Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DMGDH
NM_013391.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMGDH	NM_013391.3 link	c.2213T>G	p.Leu738Trp	missense_variant	14/16	ENST00000255189.8	NP_037523.2	Q9UI17-1B3KQ84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMGDH	ENST00000255189.8 link	c.2213T>G	p.Leu738Trp	missense_variant	14/16	1	NM_013391.3	ENSP00000255189.3		Q9UI17-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.2213T>G (p.L738W) alteration is located in exon 14 (coding exon 14) of the DMGDH gene. This alteration results from a T to G substitution at nucleotide position 2213, causing the leucine (L) at amino acid position 738 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.33

T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.010

D;D

Sift4G

Benign

0.070

T;D

Polyphen

0.96

D;.

Vest4

0.69

MutPred

0.72

Gain of catalytic residue at L738 (P = 0.0449);.;

MVP

0.85

MPC

0.79

ClinPred

0.97

GERP RS

6.1

Varity_R

0.78

gMVP

0.96

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over