5-79087640-A-G

Variant names:

• chr5-79087640-A-G
• rs597560
• NM_017614.5:c.1011-853A>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.1011-853A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,914 control chromosomes in the GnomAD database, including 22,583 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 0.53 (22583 hom., cov: 32)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.672
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 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.1011-853A>G		intron	N/A	NP_060084.2
	BHMT2	NM_001178005.2		c.819-853A>G		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.1011-853A>G		intron	N/A	ENSP00000255192.3
	BHMT2	ENST00000521567.1	TSL:2	c.819-853A>G		intron	N/A	ENSP00000430278.1
	DMGDH	ENST00000520388.5	TSL:4	n.606+16524T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80095 AN: 151796 Hom.: 22567 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.586

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.528 AC: 80153 AN: 151914 Hom.: 22583 Cov.: 32 AF XY: 0.530 AC XY: 39309 AN XY: 74232

African (AFR) AF: 0.317 AC: 13136 AN: 41492

American (AMR) AF: 0.595 AC: 9067 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1543 AN: 3466

East Asian (EAS) AF: 0.610 AC: 3153 AN: 5168

South Asian (SAS) AF: 0.519 AC: 2499 AN: 4814

European-Finnish (FIN) AF: 0.671 AC: 7067 AN: 10536

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.614 AC: 41688 AN: 67872

Other (OTH) AF: 0.534 AC: 1128 AN: 2112

Alfa AF: 0.543 Hom.: 2978

Bravo AF: 0.513

Asia WGS AF: 0.547 AC: 1900 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.66
DANN	Benign	0.40
PhyloP100		-0.67
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: rs597560; hg19: chr5-78383463;