rs526264

Positions:

• chr5-79082587-A-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHMT2	NM_017614.5	c.451-222A>T		intron_variant		ENST00000255192.8
BHMT2	NM_001178005.2	c.259-222A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHMT2	ENST00000255192.8	c.451-222A>T		intron_variant		1	NM_017614.5	P1

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

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.609

Gnomad4 OTH exome AF: 0.555

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

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.594

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.672

Gnomad4 NFE AF: 0.615

Gnomad4 OTH AF: 0.532

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.61
DANN	Benign	0.69

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: rs526264; hg19: chr5-78378410;