rs1805074

Variant names:

• chr5-79028529-A-C
• rs1805074
• NM_013391.3:c.1936T>G

Your query was ambiguous. Multiple possible variants found:

• chr5-79028529-A-C
• chr5-79028529-A-G
• chr5-79028529-A-T

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.1936T>G​(p.Ser646Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. S646P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• Publications: 0 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=0.11735651).

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.1936T>G	p.Ser646Ala	missense	Exon 12 of 16	NP_037523.2
	DMGDH	NR_104002.3		n.1521T>G		non_coding_transcript_exon	Exon 9 of 12
	DMGDH	NR_104003.3		n.1073T>G		non_coding_transcript_exon	Exon 7 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.1936T>G	p.Ser646Ala	missense	Exon 12 of 16	ENSP00000255189.3
	DMGDH	ENST00000523732.1	TSL:1	c.1453T>G	p.Ser485Ala	missense	Exon 9 of 12	ENSP00000430972.1
	DMGDH	ENST00000517853.5	TSL:2	n.*698T>G		non_coding_transcript_exon	Exon 7 of 10	ENSP00000428995.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.78	N
PhyloP100		0.081
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.47		Loss of disorder (P = 0.038)
MVP		0.62
MPC		0.12
ClinPred		0.069	T
GERP RS		2.1
Varity_R		0.097
gMVP		0.47
Mutation Taster		=86/14	polymorphism

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: rs1805074; hg19: chr5-78324352;