5-79071269-T-C

Position:

• chr5-79071269-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017614.5(BHMT2):​c.33+1454T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 152,088 control chromosomes in the GnomAD database, including 40,642 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 0.72 (40637 hom., cov: 32)
  • Exomes 𝑓: 0.79 (5 hom.)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.406

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHMT2	NM_017614.5	c.33+1454T>C		intron_variant		ENST00000255192.8
BHMT2	NM_001178005.2	c.33+1454T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHMT2	ENST00000255192.8	c.33+1454T>C		intron_variant		1	NM_017614.5	P1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110136 AN: 151956 Hom.: 40607 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.733

GnomAD4 exome AF: 0.786 AC: 11 AN: 14 Hom.: 5 AF XY: 0.625 AC XY: 5 AN XY: 8

Gnomad4 ASJ exome AF: 1.00

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.725 AC: 110209 AN: 152074 Hom.: 40637 Cov.: 32 AF XY: 0.726 AC XY: 53955 AN XY: 74350

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.677

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.789

Gnomad4 OTH AF: 0.727

Alfa AF: 0.742 Hom.: 6665

Bravo AF: 0.713

Asia WGS AF: 0.744 AC: 2587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.68

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: rs673752; hg19: chr5-78367092;