5-79044463-A-C

Variant names:

• chr5-79044463-A-C
• rs532964
• NM_013391.3:c.835T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013391.3(DMGDH):​c.835T>G​(p.Ser279Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S279P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 40 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23049864).

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.835T>G	p.Ser279Ala	missense	Exon 6 of 16	NP_037523.2
	DMGDH	NR_104002.3		n.420T>G		non_coding_transcript_exon	Exon 3 of 12
	DMGDH	NR_104003.3		n.331-11055T>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.835T>G	p.Ser279Ala	missense	Exon 6 of 16	ENSP00000255189.3
	DMGDH	ENST00000523732.1	TSL:1	c.352T>G	p.Ser118Ala	missense	Exon 3 of 12	ENSP00000430972.1
	DMGDH	ENST00000518477.5	TSL:2	n.*69T>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000427834.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.88	N
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.40		Loss of disorder (P = 0.0939)
MVP		0.50
MPC		0.12
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.33
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -1

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

Other links and lift over

dbSNP: rs532964; hg19: chr5-78340286;