chr5-79006373-C-T

Variant names:

• chr5-79006373-C-T
• rs250513
• NM_013391.3:c.2251-966G>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.2251-966G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,002 control chromosomes in the GnomAD database, including 3,396 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 0.21 (3396 hom., cov: 31)
• Consequence: DMGDH NM_013391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.621
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMGDH	NM_013391.3	c.2251-966G>A		intron_variant	Intron 14 of 15	ENST00000255189.8	NP_037523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMGDH	ENST00000255189.8	c.2251-966G>A		intron_variant	Intron 14 of 15	1	NM_013391.3	ENSP00000255189.3

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31574 AN: 151884 Hom.: 3391 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.208 AC: 31585 AN: 152002 Hom.: 3396 Cov.: 31 AF XY: 0.208 AC XY: 15447 AN XY: 74302

African (AFR) AF: 0.161 AC: 6692 AN: 41468

American (AMR) AF: 0.244 AC: 3726 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 952 AN: 3470

East Asian (EAS) AF: 0.204 AC: 1051 AN: 5156

South Asian (SAS) AF: 0.190 AC: 916 AN: 4814

European-Finnish (FIN) AF: 0.199 AC: 2101 AN: 10546

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15490 AN: 67976

Other (OTH) AF: 0.210 AC: 442 AN: 2106

Alfa AF: 0.223 Hom.: 7231

Bravo AF: 0.211

Asia WGS AF: 0.176 AC: 612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.68
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs250513; hg19: chr5-78302196;