5-79024262-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013391.3(DMGDH):c.2250+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 1,611,258 control chromosomes in the GnomAD database, including 2,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (780 hom., cov: 33)
  • Exomes 𝑓: 0.030 (2097 hom.)
• Consequence: DMGDH NM_013391.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-79024262-T-C is Benign according to our data. Variant chr5-79024262-T-C is described in ClinVar as [Benign]. Clinvar id is 380020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMGDH	NM_013391.3	c.2250+9A>G		intron_variant		ENST00000255189.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMGDH	ENST00000255189.8	c.2250+9A>G		intron_variant		1	NM_013391.3	P1
DMGDH	ENST00000523732.1	c.1767+9A>G		intron_variant		1
DMGDH	ENST00000517853.5	c.*1012+9A>G		intron_variant, NMD_transcript_variant		2
DMGDH	ENST00000518477.5	c.*1484+9A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0677 AC: 10308 AN: 152166 Hom.: 777 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0520

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0688

GnomAD3 exomes AF: 0.0484 AC: 12126 AN: 250568 Hom.: 734 AF XY: 0.0487 AC XY: 6593 AN XY: 135396

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0426

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0423

GnomAD4 exome AF: 0.0296 AC: 43114 AN: 1458974 Hom.: 2097 Cov.: 30 AF XY: 0.0315 AC XY: 22892 AN XY: 725978

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.0257

Gnomad4 ASJ exome AF: 0.0446

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0470

GnomAD4 genome AF: 0.0678 AC: 10323 AN: 152284 Hom.: 780 Cov.: 33 AF XY: 0.0675 AC XY: 5026 AN XY: 74482

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.0520

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0313 Hom.: 276

Bravo AF: 0.0740

Asia WGS AF: 0.155 AC: 538 AN: 3470

EpiCase AF: 0.0214

EpiControl AF: 0.0214

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 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. -

DMGDH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	10
Dann	Benign	0.86

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: rs2303128; hg19: chr5-78320085; COSMIC: COSV54864414; COSMIC: COSV54864414;