NM_013391.3:c.2250+3618G>A

Variant names:

• chr5-79020653-C-T
• rs921943
• NM_013391.3:c.2250+3618G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013391.3(DMGDH):​c.2250+3618G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 965,396 control chromosomes in the GnomAD database, including 42,859 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9118 hom., cov: 32)
  • Exomes 𝑓: 0.28 (33741 hom.)
• Consequence: DMGDH NM_013391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 35 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	NM_013391.3	MANE Select	c.2250+3618G>A		intron	N/A	NP_037523.2
	DMGDH	NR_104002.3		n.*2G>A		downstream_gene	N/A
	DMGDH	NR_104003.3		n.*2G>A		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.2250+3618G>A		intron	N/A	ENSP00000255189.3
	DMGDH	ENST00000523732.1	TSL:1	c.*954G>A		downstream_gene	N/A	ENSP00000430972.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50294 AN: 151794 Hom.: 9108 Cov.: 32

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.284 AC: 231187 AN: 813484 Hom.: 33741 Cov.: 16 AF XY: 0.284 AC XY: 106952 AN XY: 376370

African (AFR) AF: 0.489 AC: 7478 AN: 15282

American (AMR) AF: 0.186 AC: 177 AN: 954

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1619 AN: 5024

East Asian (EAS) AF: 0.154 AC: 545 AN: 3536

South Asian (SAS) AF: 0.303 AC: 4852 AN: 15996

European-Finnish (FIN) AF: 0.285 AC: 77 AN: 270

Middle Eastern (MID) AF: 0.315 AC: 495 AN: 1570

European-Non Finnish (NFE) AF: 0.280 AC: 208585 AN: 744174

Other (OTH) AF: 0.276 AC: 7359 AN: 26678

GnomAD4 genome AF: 0.331 AC: 50335 AN: 151912 Hom.: 9118 Cov.: 32 AF XY: 0.328 AC XY: 24368 AN XY: 74242

African (AFR) AF: 0.482 AC: 19939 AN: 41378

American (AMR) AF: 0.232 AC: 3541 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3468

East Asian (EAS) AF: 0.149 AC: 768 AN: 5160

South Asian (SAS) AF: 0.289 AC: 1395 AN: 4822

European-Finnish (FIN) AF: 0.279 AC: 2938 AN: 10540

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19787 AN: 67946

Other (OTH) AF: 0.310 AC: 655 AN: 2110

Alfa AF: 0.309 Hom.: 12680

Bravo AF: 0.331

Asia WGS AF: 0.210 AC: 731 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.58
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs921943; hg19: chr5-78316476;