5-79120593-C-T

Variant names:

• chr5-79120593-C-T
• rs567754
• NM_001713.3:c.477+52C>T

Variant summary

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

The NM_001713.3(BHMT):​c.477+52C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,506,308 control chromosomes in the GnomAD database, including 90,396 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 0.28 (7407 hom., cov: 33)
  • Exomes 𝑓: 0.34 (82989 hom.)
• Consequence: BHMT NM_001713.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.403
• Publications: 39 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT	NM_001713.3	c.477+52C>T		intron_variant	Intron 4 of 7	ENST00000274353.10	NP_001704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10	c.477+52C>T		intron_variant	Intron 4 of 7	1	NM_001713.3	ENSP00000274353.5

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42924 AN: 152044 Hom.: 7401 Cov.: 33

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.349 AC: 62467 AN: 178910 AF XY: 0.357

Gnomad AFR exome AF: 0.0633

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.436

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.345 AC: 466746 AN: 1354146 Hom.: 82989 Cov.: 22 AF XY: 0.348 AC XY: 231904 AN XY: 667294

African (AFR) AF: 0.0556 AC: 1666 AN: 29988

American (AMR) AF: 0.405 AC: 12542 AN: 30974

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 6619 AN: 21412

East Asian (EAS) AF: 0.423 AC: 15931 AN: 37634

South Asian (SAS) AF: 0.430 AC: 29475 AN: 68476

European-Finnish (FIN) AF: 0.408 AC: 20592 AN: 50466

Middle Eastern (MID) AF: 0.374 AC: 1442 AN: 3858

European-Non Finnish (NFE) AF: 0.341 AC: 359437 AN: 1055496

Other (OTH) AF: 0.341 AC: 19042 AN: 55842

GnomAD4 genome AF: 0.282 AC: 42937 AN: 152162 Hom.: 7407 Cov.: 33 AF XY: 0.292 AC XY: 21753 AN XY: 74406

African (AFR) AF: 0.0734 AC: 3049 AN: 41540

American (AMR) AF: 0.383 AC: 5851 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1084 AN: 3470

East Asian (EAS) AF: 0.423 AC: 2185 AN: 5170

South Asian (SAS) AF: 0.436 AC: 2106 AN: 4828

European-Finnish (FIN) AF: 0.434 AC: 4591 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22907 AN: 67984

Other (OTH) AF: 0.301 AC: 636 AN: 2110

Alfa AF: 0.324 Hom.: 15238

Bravo AF: 0.269

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		-0.40
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: rs567754; hg19: chr5-78416416; COSMIC: COSV57155795; COSMIC: COSV57155795;