rs476620

Variant names:

• chr5-79058623-G-A
• rs476620
• NM_013391.3:c.277-2715C>T

Variant summary

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

The NM_013391.3(DMGDH):​c.277-2715C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 152,002 control chromosomes in the GnomAD database, including 22,796 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 0.52 (22796 hom., cov: 32)
• Consequence: DMGDH NM_013391.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.478
• Publications: 5 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 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.277-2715C>T		intron	N/A	NP_037523.2	Q9UI17-1
	DMGDH	NR_104002.3		n.330+4990C>T		intron	N/A
	DMGDH	NR_104003.3		n.330+4990C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.277-2715C>T		intron	N/A	ENSP00000255189.3	Q9UI17-1
	DMGDH	ENST00000895914.1		c.304-2715C>T		intron	N/A	ENSP00000565973.1
	DMGDH	ENST00000895909.1		c.184-2715C>T		intron	N/A	ENSP00000565968.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79688 AN: 151884 Hom.: 22781 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.525 AC: 79728 AN: 152002 Hom.: 22796 Cov.: 32 AF XY: 0.527 AC XY: 39186 AN XY: 74294

African (AFR) AF: 0.279 AC: 11562 AN: 41450

American (AMR) AF: 0.600 AC: 9169 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1577 AN: 3466

East Asian (EAS) AF: 0.639 AC: 3310 AN: 5176

South Asian (SAS) AF: 0.525 AC: 2531 AN: 4822

European-Finnish (FIN) AF: 0.675 AC: 7126 AN: 10558

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42455 AN: 67950

Other (OTH) AF: 0.535 AC: 1127 AN: 2108

Alfa AF: 0.581 Hom.: 33718

Bravo AF: 0.509

Asia WGS AF: 0.565 AC: 1961 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.28
DANN	Benign	0.59
PhyloP100		-0.48
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: rs476620; hg19: chr5-78354446;