rs4703772

Positions:

• chr5-79126212-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001713.3(BHMT):​c.792C>T​(p.Leu264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,613,508 control chromosomes in the GnomAD database, including 969 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 0.012 (135 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (834 hom.)
• Consequence: BHMT NM_001713.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154

Genes affected

BHMT (HGNC:1047): (betaine--homocysteine S-methyltransferase) This gene encodes a cytosolic enzyme that catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine, respectively. Defects in this gene could lead to hyperhomocyst(e)inemia, but such a defect has not yet been observed. [provided by RefSeq, Jul 2008]

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=-0.154 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHMT	NM_001713.3	c.792C>T	p.Leu264=	synonymous_variant	6/8	ENST00000274353.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHMT	ENST00000274353.10	c.792C>T	p.Leu264=	synonymous_variant	6/8	1	NM_001713.3	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1859 AN: 152182 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0276 AC: 6934 AN: 250838 Hom.: 684 AF XY: 0.0214 AC XY: 2909 AN XY: 135646

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.00658 AC: 9615 AN: 1461208 Hom.: 834 Cov.: 31 AF XY: 0.00571 AC XY: 4153 AN XY: 726836

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.0122 AC: 1858 AN: 152300 Hom.: 135 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74468

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0967

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00717 Hom.: 112

Bravo AF: 0.0210

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.2
DANN	Benign	0.54

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: rs4703772; hg19: chr5-78422035;