rs1805073

Variant names:

• chr5-79030927-G-C
• rs1805073
• NM_013391.3:c.1589C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-79030927-G-C
• chr5-79030927-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A530E) has been classified as Uncertain significance.

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.09
• Publications: 37 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 380064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	NM_013391.3	MANE Select	c.1589C>G	p.Ala530Gly	missense	Exon 10 of 16	NP_037523.2	Q9UI17-1
	DMGDH	NR_104002.3		n.1174C>G		non_coding_transcript_exon	Exon 7 of 12
	DMGDH	NR_104003.3		n.726C>G		non_coding_transcript_exon	Exon 5 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.1589C>G	p.Ala530Gly	missense	Exon 10 of 16	ENSP00000255189.3	Q9UI17-1
	DMGDH	ENST00000523732.1	TSL:1	c.1106C>G	p.Ala369Gly	missense	Exon 7 of 12	ENSP00000430972.1	Q8TCC6
	DMGDH	ENST00000895914.1		c.1616C>G	p.Ala539Gly	missense	Exon 11 of 17	ENSP00000565973.1

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

GnomAD2 exomes AF: 0.274 AC: 68891 AN: 251256 AF XY: 0.277

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 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

African (AFR) AF: 0.477 AC: 15976 AN: 33470

American (AMR) AF: 0.164 AC: 7331 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8398 AN: 26136

East Asian (EAS) AF: 0.145 AC: 5750 AN: 39700

South Asian (SAS) AF: 0.300 AC: 25842 AN: 86246

European-Finnish (FIN) AF: 0.269 AC: 14392 AN: 53408

Middle Eastern (MID) AF: 0.325 AC: 1877 AN: 5768

European-Non Finnish (NFE) AF: 0.286 AC: 318507 AN: 1111744

Other (OTH) AF: 0.284 AC: 17149 AN: 60380

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

African (AFR) AF: 0.477 AC: 19747 AN: 41430

American (AMR) AF: 0.230 AC: 3510 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1051 AN: 3470

East Asian (EAS) AF: 0.147 AC: 758 AN: 5166

South Asian (SAS) AF: 0.290 AC: 1397 AN: 4812

European-Finnish (FIN) AF: 0.279 AC: 2940 AN: 10554

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19828 AN: 67976

Other (OTH) AF: 0.307 AC: 649 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		6.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	5.2	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=97/3	polymorphism (auto)

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