rs526264

Variant names:

• chr5-79082587-A-T
• rs526264
• NM_017614.5:c.451-222A>T

Variant summary

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

The NM_017614.5(BHMT2):​c.451-222A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 389,306 control chromosomes in the GnomAD database, including 63,533 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 0.52 (22423 hom., cov: 32)
  • Exomes 𝑓: 0.58 (41110 hom.)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017614.5. 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
	BHMT2	NM_017614.5	MANE Select	c.451-222A>T		intron	N/A	NP_060084.2
	BHMT2	NM_001178005.2		c.259-222A>T		intron	N/A	NP_001171476.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.451-222A>T		intron	N/A	ENSP00000255192.3
	BHMT2	ENST00000523046.1	TSL:4	n.196A>T		non_coding_transcript_exon	Exon 1 of 2
	BHMT2	ENST00000521567.1	TSL:2	c.259-222A>T		intron	N/A	ENSP00000430278.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79564 AN: 151900 Hom.: 22409 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.580 AC: 137627 AN: 237288 Hom.: 41110 Cov.: 4 AF XY: 0.579 AC XY: 70883 AN XY: 122478

African (AFR) AF: 0.286 AC: 2049 AN: 7172

American (AMR) AF: 0.573 AC: 4918 AN: 8590

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 3482 AN: 8060

East Asian (EAS) AF: 0.535 AC: 9488 AN: 17730

South Asian (SAS) AF: 0.490 AC: 5415 AN: 11046

European-Finnish (FIN) AF: 0.654 AC: 9830 AN: 15032

Middle Eastern (MID) AF: 0.527 AC: 576 AN: 1094

European-Non Finnish (NFE) AF: 0.609 AC: 93825 AN: 154072

Other (OTH) AF: 0.555 AC: 8044 AN: 14492

GnomAD4 genome AF: 0.524 AC: 79615 AN: 152018 Hom.: 22423 Cov.: 32 AF XY: 0.526 AC XY: 39072 AN XY: 74300

African (AFR) AF: 0.301 AC: 12497 AN: 41460

American (AMR) AF: 0.594 AC: 9076 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1544 AN: 3470

East Asian (EAS) AF: 0.609 AC: 3151 AN: 5170

South Asian (SAS) AF: 0.519 AC: 2498 AN: 4816

European-Finnish (FIN) AF: 0.672 AC: 7089 AN: 10556

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.615 AC: 41764 AN: 67954

Other (OTH) AF: 0.532 AC: 1124 AN: 2112

Alfa AF: 0.550 Hom.: 2923

Bravo AF: 0.508

Asia WGS AF: 0.544 AC: 1892 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.61
DANN	Benign	0.69
PhyloP100		-1.3
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: rs526264; hg19: chr5-78378410;