rs1805074

chr5-79028529-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013391.3(DMGDH):c.1936T>C(p.Ser646Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,646 control chromosomes in the GnomAD database, including 69,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (8780 hom., cov: 31)
  • Exomes 𝑓: 0.28 (61041 hom.)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0810

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9748678E-4).
• BP6: Variant 5-79028529-A-G is Benign according to our data. Variant chr5-79028529-A-G is described in ClinVar as [Benign]. Clinvar id is 380066.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMGDH	NM_013391.3	c.1936T>C	p.Ser646Pro	missense_variant	12/16	ENST00000255189.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMGDH	ENST00000255189.8	c.1936T>C	p.Ser646Pro	missense_variant	12/16	1	NM_013391.3	P1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49564 AN: 151820 Hom.: 8771 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.274 AC: 68746 AN: 251270 Hom.: 10276 AF XY: 0.277 AC XY: 37636 AN XY: 135786

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.301

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.284 AC: 414880 AN: 1461706 Hom.: 61041 Cov.: 36 AF XY: 0.285 AC XY: 206944 AN XY: 727166

Gnomad4 AFR exome AF: 0.466

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.326 AC: 49603 AN: 151940 Hom.: 8780 Cov.: 31 AF XY: 0.324 AC XY: 24056 AN XY: 74270

Gnomad4 AFR AF: 0.465

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.307

Alfa AF: 0.297 Hom.: 15841

Bravo AF: 0.325

TwinsUK AF: 0.280 AC: 1039

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.455 AC: 2003

ESP6500EA AF: 0.287 AC: 2466

ExAC AF: 0.280 AC: 33968

Asia WGS AF: 0.210 AC: 731 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.00030	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.15
Sift	Benign	0.17	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;.
Vest4		0.040
MPC		0.18
ClinPred		0.0073	T
GERP RS		2.1
Varity_R		0.55
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805074; hg19: chr5-78324352; COSMIC: COSV54861785;