NM_013391.3:c.2191-956T>C

Variant names:

• chr5-79025286-A-G
• rs2431332
• NM_013391.3:c.2191-956T>C

Variant summary

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

The NM_013391.3(DMGDH):​c.2191-956T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,074 control chromosomes in the GnomAD database, including 2,961 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 0.18 (2961 hom., cov: 32)
• Consequence: DMGDH NM_013391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.494
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	NM_013391.3	MANE Select	c.2191-956T>C		intron	N/A	NP_037523.2	Q9UI17-1
	DMGDH	NR_104002.3		n.1776-956T>C		intron	N/A
	DMGDH	NR_104003.3		n.1328-956T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.2191-956T>C		intron	N/A	ENSP00000255189.3	Q9UI17-1
	DMGDH	ENST00000523732.1	TSL:1	c.1708-956T>C		intron	N/A	ENSP00000430972.1	Q8TCC6
	DMGDH	ENST00000895914.1		c.2218-956T>C		intron	N/A	ENSP00000565973.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26967 AN: 151954 Hom.: 2959 Cov.: 32

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.177 AC: 26967 AN: 152074 Hom.: 2961 Cov.: 32 AF XY: 0.176 AC XY: 13101 AN XY: 74348

African (AFR) AF: 0.0598 AC: 2484 AN: 41528

American (AMR) AF: 0.204 AC: 3113 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 948 AN: 3470

East Asian (EAS) AF: 0.0720 AC: 372 AN: 5168

South Asian (SAS) AF: 0.169 AC: 812 AN: 4798

European-Finnish (FIN) AF: 0.208 AC: 2202 AN: 10588

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16423 AN: 67930

Other (OTH) AF: 0.181 AC: 382 AN: 2108

Alfa AF: 0.225 Hom.: 7833

Bravo AF: 0.172

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.4
DANN	Benign	0.49
PhyloP100		0.49
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: rs2431332; hg19: chr5-78321109;