rs57906668

Variant names:

• chr5-79077322-T-C
• rs57906668
• NM_017614.5:c.34-158T>C

Variant summary

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

The NM_017614.5(BHMT2):​c.34-158T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,178 control chromosomes in the GnomAD database, including 1,418 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 0.13 (1418 hom., cov: 32)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 2 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT2	NM_017614.5	c.34-158T>C		intron_variant	Intron 1 of 7	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2	c.34-158T>C		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.34-158T>C		intron_variant	Intron 1 of 7	1	NM_017614.5	ENSP00000255192.3

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19043 AN: 152060 Hom.: 1419 Cov.: 32

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.125 AC: 19046 AN: 152178 Hom.: 1418 Cov.: 32 AF XY: 0.123 AC XY: 9144 AN XY: 74402

African (AFR) AF: 0.0684 AC: 2841 AN: 41528

American (AMR) AF: 0.103 AC: 1577 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3472

East Asian (EAS) AF: 0.00655 AC: 34 AN: 5188

South Asian (SAS) AF: 0.156 AC: 751 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10560

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11403 AN: 68012

Other (OTH) AF: 0.139 AC: 293 AN: 2112

Alfa AF: 0.162 Hom.: 897

Bravo AF: 0.120

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0040
DANN	Benign	0.18
PhyloP100		-2.0
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: rs57906668; hg19: chr5-78373145;