rs557302

Variant names:

• chr5-79081511-A-G
• rs557302
• NM_017614.5:c.450+633A>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.450+633A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 152,000 control chromosomes in the GnomAD database, including 15,719 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 0.43 (15719 hom., cov: 32)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.756
• Publications: 12 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT2	NM_017614.5	c.450+633A>G		intron_variant	Intron 4 of 7	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2	c.259-1298A>G		intron_variant	Intron 3 of 6		NP_001171476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT2	ENST00000255192.8	c.450+633A>G		intron_variant	Intron 4 of 7	1	NM_017614.5	ENSP00000255192.3
BHMT2	ENST00000521567.1	c.259-1298A>G		intron_variant	Intron 3 of 6	2		ENSP00000430278.1
BHMT2	ENST00000519743.1	n.*211+633A>G		intron_variant	Intron 5 of 6	5		ENSP00000430155.1
DMGDH	ENST00000520388.5	n.606+22653T>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65433 AN: 151882 Hom.: 15711 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.431 AC: 65456 AN: 152000 Hom.: 15719 Cov.: 32 AF XY: 0.434 AC XY: 32267 AN XY: 74270

African (AFR) AF: 0.202 AC: 8367 AN: 41466

American (AMR) AF: 0.529 AC: 8093 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1316 AN: 3472

East Asian (EAS) AF: 0.609 AC: 3142 AN: 5158

South Asian (SAS) AF: 0.455 AC: 2185 AN: 4798

European-Finnish (FIN) AF: 0.576 AC: 6084 AN: 10560

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34562 AN: 67946

Other (OTH) AF: 0.447 AC: 943 AN: 2110

Alfa AF: 0.448 Hom.: 6127

Bravo AF: 0.419

Asia WGS AF: 0.514 AC: 1790 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.78
PhyloP100		0.76
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: rs557302; hg19: chr5-78377334;