5-79030927-G-C

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.1589C>G(p.Ala530Gly) variant causes a missense change. The variant allele was found at a frequency of 0.288 in 1,613,572 control chromosomes in the GnomAD database, including 70,233 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 (9030 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61203 hom.)
• Consequence: DMGDH NM_013391.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.09

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=0.005518168).
• BP6: Variant 5-79030927-G-C is Benign according to our data. Variant chr5-79030927-G-C is described in ClinVar as [Benign]. Clinvar id is 380064.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMGDH	NM_013391.3	c.1589C>G	p.Ala530Gly	missense_variant	10/16	ENST00000255189.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMGDH	ENST00000255189.8	c.1589C>G	p.Ala530Gly	missense_variant	10/16	1	NM_013391.3	P1
DMGDH	ENST00000523732.1	c.1106C>G	p.Ala369Gly	missense_variant	7/12	1
DMGDH	ENST00000517853.5	c.*351C>G		3_prime_UTR_variant, NMD_transcript_variant	5/10	2
DMGDH	ENST00000518477.5	c.*823C>G		3_prime_UTR_variant, NMD_transcript_variant	7/12	2

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50103 AN: 151884 Hom.: 9022 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.274 AC: 68891 AN: 251256 Hom.: 10333 AF XY: 0.277 AC XY: 37674 AN XY: 135788

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.150

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.284 AC: 415222 AN: 1461570 Hom.: 61203 Cov.: 35 AF XY: 0.285 AC XY: 207060 AN XY: 727090

Gnomad4 AFR exome AF: 0.477

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: 0.286

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.330 AC: 50141 AN: 152002 Hom.: 9030 Cov.: 32 AF XY: 0.327 AC XY: 24307 AN XY: 74306

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.279

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.307

Alfa AF: 0.277 Hom.: 4398

Bravo AF: 0.329

TwinsUK AF: 0.280 AC: 1040

ALSPAC AF: 0.292 AC: 1125

ESP6500AA AF: 0.465 AC: 2049

ESP6500EA AF: 0.287 AC: 2467

ExAC AF: 0.281 AC: 34078

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	0.054
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.81
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;.
MutationTaster	Benign	0.96	P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	5.2	N;N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.086
MPC		0.14
ClinPred		0.0055	T
GERP RS		5.9
Varity_R		0.34
gMVP		0.84

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: rs1805073; hg19: chr5-78326750; COSMIC: COSV54861827; COSMIC: COSV54861827;