5-79090022-T-G

Variant names:

• chr5-79090022-T-G
• rs10944
• NM_017614.5:c.*1448T>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.*1448T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 152,132 control chromosomes in the GnomAD database, including 15,120 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 0.41 (15120 hom., cov: 32)
• Consequence: BHMT2 NM_017614.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.565
• Publications: 18 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT2	NM_017614.5	c.*1448T>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2	c.*1448T>G		3_prime_UTR_variant	Exon 7 of 7		NP_001171476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT2	ENST00000255192.8	c.*1448T>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_017614.5	ENSP00000255192.3
DMGDH	ENST00000520388.5	n.606+14142A>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61647 AN: 152014 Hom.: 15114 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.432

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

GnomAD4 genome AF: 0.405 AC: 61654 AN: 152132 Hom.: 15120 Cov.: 32 AF XY: 0.410 AC XY: 30521 AN XY: 74380

African (AFR) AF: 0.113 AC: 4696 AN: 41546

American (AMR) AF: 0.522 AC: 7966 AN: 15274

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

East Asian (EAS) AF: 0.610 AC: 3161 AN: 5180

South Asian (SAS) AF: 0.456 AC: 2197 AN: 4822

European-Finnish (FIN) AF: 0.577 AC: 6096 AN: 10568

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34551 AN: 67956

Other (OTH) AF: 0.430 AC: 908 AN: 2110

Alfa AF: 0.473 Hom.: 28655

Bravo AF: 0.390

Asia WGS AF: 0.503 AC: 1750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.72
PhyloP100		0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10944; hg19: chr5-78385845;