rs2461248

Variant names:

• chr5-79104608-A-T
• rs2461248
• ENST00000520388.5:n.492-330T>A

Variant summary

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

The ENST00000520388.5(DMGDH):​n.492-330T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 151,986 control chromosomes in the GnomAD database, including 15,317 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 0.41 (15317 hom., cov: 31)
• Consequence: DMGDH ENST00000520388.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMGDH	ENST00000520388.5	n.492-330T>A		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62581 AN: 151868 Hom.: 15310 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.437

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.412 AC: 62591 AN: 151986 Hom.: 15317 Cov.: 31 AF XY: 0.417 AC XY: 30932 AN XY: 74242

African (AFR) AF: 0.131 AC: 5415 AN: 41476

American (AMR) AF: 0.526 AC: 8040 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1316 AN: 3468

East Asian (EAS) AF: 0.607 AC: 3142 AN: 5176

South Asian (SAS) AF: 0.457 AC: 2191 AN: 4798

European-Finnish (FIN) AF: 0.578 AC: 6078 AN: 10516

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34725 AN: 67966

Other (OTH) AF: 0.435 AC: 917 AN: 2108

Alfa AF: 0.440 Hom.: 1942

Bravo AF: 0.397

Asia WGS AF: 0.505 AC: 1758 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.62
DANN	Benign	0.38
PhyloP100		-0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2461248; hg19: chr5-78400431;