chr5-79070503-T-G

Variant names:

• chr5-79070503-T-G
• rs670220
• NM_017614.5:c.33+688T>G

Variant summary

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

The NM_017614.5(BHMT2):​c.33+688T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 151,962 control chromosomes in the GnomAD database, including 40,610 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (40610 hom., cov: 30)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538
• Publications: 8 publications found

Genes affected

BHMT2 (HGNC:1048): (betaine--homocysteine S-methyltransferase 2) Homocysteine is a sulfur-containing amino acid that plays a crucial role in methylation reactions. Transfer of the methyl group from betaine to homocysteine creates methionine, which donates the methyl group to methylate DNA, proteins, lipids, and other intracellular metabolites. The protein encoded by this gene is one of two methyl transferases that can catalyze the transfer of the methyl group from betaine to homocysteine. Anomalies in homocysteine metabolism have been implicated in disorders ranging from vascular disease to neural tube birth defects such as spina bifida. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

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 (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT2	NM_017614.5	c.33+688T>G		intron_variant	Intron 1 of 7	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2	c.33+688T>G		intron_variant	Intron 1 of 6		NP_001171476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT2	ENST00000255192.8	c.33+688T>G		intron_variant	Intron 1 of 7	1	NM_017614.5	ENSP00000255192.3

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110056 AN: 151844 Hom.: 40579 Cov.: 30

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.733

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.725 AC: 110128 AN: 151962 Hom.: 40610 Cov.: 30 AF XY: 0.726 AC XY: 53913 AN XY: 74292

African (AFR) AF: 0.574 AC: 23750 AN: 41408

American (AMR) AF: 0.756 AC: 11548 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2351 AN: 3468

East Asian (EAS) AF: 0.792 AC: 4081 AN: 5152

South Asian (SAS) AF: 0.760 AC: 3658 AN: 4810

European-Finnish (FIN) AF: 0.809 AC: 8545 AN: 10560

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53610 AN: 67988

Other (OTH) AF: 0.727 AC: 1525 AN: 2098

Alfa AF: 0.760 Hom.: 30702

Bravo AF: 0.713

Asia WGS AF: 0.743 AC: 2584 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.41
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs670220; hg19: chr5-78366326;