5-79005349-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_013391.3(DMGDH):c.2309G>A(p.Arg770Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,942 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.82

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=0.0711869).
• BP6: Variant 5-79005349-C-T is Benign according to our data. Variant chr5-79005349-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-79005349-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMGDH	NM_013391.3	c.2309G>A	p.Arg770Gln	missense_variant	15/16	ENST00000255189.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMGDH	ENST00000255189.8	c.2309G>A	p.Arg770Gln	missense_variant	15/16	1	NM_013391.3	P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00183 AC: 458 AN: 250906 Hom.: 3 AF XY: 0.00183 AC XY: 248 AN XY: 135554

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00148

Gnomad FIN exome AF: 0.000972

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00222 AC: 3241 AN: 1461640 Hom.: 8 Cov.: 32 AF XY: 0.00222 AC XY: 1617 AN XY: 727074

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74470

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00191

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00279

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DMGDH: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.071	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.57
Sift	Benign	0.15	T
Sift4G	Benign	0.075	T
Polyphen		0.95	P
Vest4		0.84
MVP		0.86
MPC		0.67
ClinPred		0.032	T
GERP RS		4.8
Varity_R		0.34
gMVP		0.91

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: rs41272262; hg19: chr5-78301172;