NM_001713.3:c.716G>A

Variant names:

• chr5-79126136-G-A
• rs3733890
• NM_001713.3:c.716G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001713.3(BHMT):​c.716G>A​(p.Arg239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,612,820 control chromosomes in the GnomAD database, including 69,618 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (5975 hom., cov: 31)
  • Exomes 𝑓: 0.29 (63643 hom.)
• Consequence: BHMT NM_001713.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86
• Publications: 173 publications found

Genes affected

BHMT (HGNC:1047): (betaine--homocysteine S-methyltransferase) This gene encodes a cytosolic enzyme that catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine, respectively. Defects in this gene could lead to hyperhomocyst(e)inemia, but such a defect has not yet been observed. [provided by RefSeq, Jul 2008]

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020504296).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001713.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT	NM_001713.3	MANE Select	c.716G>A	p.Arg239Gln	missense	Exon 6 of 8	NP_001704.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT	ENST00000274353.10	TSL:1 MANE Select	c.716G>A	p.Arg239Gln	missense	Exon 6 of 8	ENSP00000274353.5
	BHMT	ENST00000524080.1	TSL:2	c.257G>A	p.Arg86Gln	missense	Exon 3 of 5	ENSP00000428240.1
	BHMT	ENST00000521279.1	TSL:2	n.176G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42017 AN: 151846 Hom.: 5975 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.302 AC: 75970 AN: 251278 AF XY: 0.302

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.293 AC: 427841 AN: 1460856 Hom.: 63643 Cov.: 35 AF XY: 0.293 AC XY: 212945 AN XY: 726532

African (AFR) AF: 0.220 AC: 7362 AN: 33474

American (AMR) AF: 0.378 AC: 16895 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 8788 AN: 26126

East Asian (EAS) AF: 0.271 AC: 10763 AN: 39660

South Asian (SAS) AF: 0.286 AC: 24688 AN: 86208

European-Finnish (FIN) AF: 0.244 AC: 13026 AN: 53402

Middle Eastern (MID) AF: 0.307 AC: 1771 AN: 5764

European-Non Finnish (NFE) AF: 0.294 AC: 327145 AN: 1111188

Other (OTH) AF: 0.288 AC: 17403 AN: 60356

GnomAD4 genome AF: 0.277 AC: 42027 AN: 151964 Hom.: 5975 Cov.: 31 AF XY: 0.276 AC XY: 20510 AN XY: 74256

African (AFR) AF: 0.221 AC: 9164 AN: 41472

American (AMR) AF: 0.341 AC: 5206 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1107 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1638 AN: 5168

South Asian (SAS) AF: 0.281 AC: 1346 AN: 4794

European-Finnish (FIN) AF: 0.240 AC: 2528 AN: 10534

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20085 AN: 67940

Other (OTH) AF: 0.301 AC: 637 AN: 2114

Alfa AF: 0.298 Hom.: 31022

Bravo AF: 0.285

TwinsUK AF: 0.309 AC: 1144

ALSPAC AF: 0.300 AC: 1155

ESP6500AA AF: 0.222 AC: 980

ESP6500EA AF: 0.300 AC: 2584

ExAC AF: 0.295 AC: 35825

Asia WGS AF: 0.273 AC: 947 AN: 3478

EpiCase AF: 0.312

EpiControl AF: 0.312

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.058
Sift	Benign	0.051	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0	B
Vest4		0.084
MPC		0.11
ClinPred		0.011	T
GERP RS		3.5
Varity_R		0.058
gMVP		0.54
Mutation Taster		=100/0	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: rs3733890; hg19: chr5-78421959; COSMIC: COSV57153716;