rs542852

Variant names:

• chr5-79113573-T-C
• rs542852
• NM_001713.3:c.33+1655T>C

Variant summary

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

The NM_001713.3(BHMT):​c.33+1655T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 152,060 control chromosomes in the GnomAD database, including 30,300 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 0.63 (30300 hom., cov: 33)
• Consequence: BHMT NM_001713.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.99
• Publications: 7 publications found

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]

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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT	NM_001713.3	c.33+1655T>C		intron_variant	Intron 1 of 7	ENST00000274353.10	NP_001704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10	c.33+1655T>C		intron_variant	Intron 1 of 7	1	NM_001713.3	ENSP00000274353.5

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95691 AN: 151942 Hom.: 30258 Cov.: 33

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.670

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.625

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

GnomAD4 genome AF: 0.630 AC: 95791 AN: 152060 Hom.: 30300 Cov.: 33 AF XY: 0.631 AC XY: 46901 AN XY: 74314

African (AFR) AF: 0.605 AC: 25066 AN: 41464

American (AMR) AF: 0.644 AC: 9836 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1981 AN: 3472

East Asian (EAS) AF: 0.688 AC: 3563 AN: 5176

South Asian (SAS) AF: 0.597 AC: 2883 AN: 4826

European-Finnish (FIN) AF: 0.678 AC: 7146 AN: 10540

Middle Eastern (MID) AF: 0.676 AC: 196 AN: 290

European-Non Finnish (NFE) AF: 0.634 AC: 43117 AN: 67984

Other (OTH) AF: 0.624 AC: 1319 AN: 2114

Alfa AF: 0.623 Hom.: 11289

Bravo AF: 0.627

Asia WGS AF: 0.670 AC: 2327 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.40
DANN	Benign	0.79
PhyloP100		-5.0
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: rs542852; hg19: chr5-78409396; COSMIC: COSV57153900;