rs2253262

Variant names:

• chr5-79055813-A-C
• rs2253262
• NM_013391.3:c.372T>G

Your query was ambiguous. Multiple possible variants found:

• chr5-79055813-A-C
• chr5-79055813-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013391.3(DMGDH):​c.372T>G​(p.Gly124Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 1,579,890 control chromosomes in the GnomAD database, including 325,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31077 hom., cov: 32)
  • Exomes 𝑓: 0.64 (294171 hom.)
• Consequence: DMGDH NM_013391.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.573
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-79055813-A-C is Benign according to our data. Variant chr5-79055813-A-C is described in ClinVar as Benign. ClinVar VariationId is 380019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.573 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 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.372T>G	p.Gly124Gly	synonymous	Exon 3 of 16	NP_037523.2	Q9UI17-1
	DMGDH	NR_104002.3		n.330+7800T>G		intron	N/A
	DMGDH	NR_104003.3		n.330+7800T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMGDH	ENST00000255189.8	TSL:1 MANE Select	c.372T>G	p.Gly124Gly	synonymous	Exon 3 of 16	ENSP00000255189.3	Q9UI17-1
	DMGDH	ENST00000895914.1		c.399T>G	p.Gly133Gly	synonymous	Exon 4 of 17	ENSP00000565973.1
	DMGDH	ENST00000895909.1		c.279T>G	p.Gly93Gly	synonymous	Exon 3 of 16	ENSP00000565968.1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96855 AN: 151910 Hom.: 31038 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.643 AC: 160556 AN: 249518 AF XY: 0.644

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.633

Gnomad ASJ exome AF: 0.538

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.640 AC: 913788 AN: 1427862 Hom.: 294171 Cov.: 27 AF XY: 0.640 AC XY: 455574 AN XY: 712294

African (AFR) AF: 0.596 AC: 19581 AN: 32858

American (AMR) AF: 0.627 AC: 27961 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 14028 AN: 25958

East Asian (EAS) AF: 0.764 AC: 30168 AN: 39462

South Asian (SAS) AF: 0.623 AC: 53300 AN: 85566

European-Finnish (FIN) AF: 0.664 AC: 35414 AN: 53302

Middle Eastern (MID) AF: 0.643 AC: 3675 AN: 5718

European-Non Finnish (NFE) AF: 0.640 AC: 691637 AN: 1081136

Other (OTH) AF: 0.641 AC: 38024 AN: 59300

GnomAD4 genome AF: 0.638 AC: 96943 AN: 152028 Hom.: 31077 Cov.: 32 AF XY: 0.639 AC XY: 47505 AN XY: 74324

African (AFR) AF: 0.605 AC: 25069 AN: 41424

American (AMR) AF: 0.652 AC: 9966 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1904 AN: 3470

East Asian (EAS) AF: 0.779 AC: 4031 AN: 5172

South Asian (SAS) AF: 0.629 AC: 3034 AN: 4826

European-Finnish (FIN) AF: 0.678 AC: 7155 AN: 10558

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43529 AN: 67984

Other (OTH) AF: 0.639 AC: 1346 AN: 2106

Alfa AF: 0.632 Hom.: 46962

Bravo AF: 0.635

Asia WGS AF: 0.725 AC: 2524 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.0
DANN	Benign	0.73
PhyloP100		-0.57
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2253262; hg19: chr5-78351636; COSMIC: COSV107297052; COSMIC: COSV107297052;