5-79118514-T-C

Variant names:

• chr5-79118514-T-C
• rs506500
• NM_001713.3:c.167-745T>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.167-745T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 152,132 control chromosomes in the GnomAD database, including 41,875 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 0.74 (41875 hom., cov: 33)
• Consequence: BHMT NM_001713.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.908
• Publications: 15 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)

LOC124901012 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT	NM_001713.3	c.167-745T>C		intron_variant	Intron 2 of 7	ENST00000274353.10	NP_001704.2
LOC124901012	XR_007058837.1	n.79+723A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10	c.167-745T>C		intron_variant	Intron 2 of 7	1	NM_001713.3	ENSP00000274353.5
BHMT	ENST00000524080.1	c.166+2615T>C		intron_variant	Intron 2 of 4	2		ENSP00000428240.1
DMGDH	ENST00000520388.5	n.491+1827A>G		intron_variant	Intron 3 of 4	4
BHMT	ENST00000520703.1	n.244-745T>C		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.738 AC: 112259 AN: 152014 Hom.: 41827 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.764

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

GnomAD4 genome AF: 0.739 AC: 112365 AN: 152132 Hom.: 41875 Cov.: 33 AF XY: 0.745 AC XY: 55397 AN XY: 74368

African (AFR) AF: 0.786 AC: 32630 AN: 41512

American (AMR) AF: 0.804 AC: 12286 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 2619 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4719 AN: 5184

South Asian (SAS) AF: 0.848 AC: 4076 AN: 4806

European-Finnish (FIN) AF: 0.702 AC: 7412 AN: 10558

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46119 AN: 67998

Other (OTH) AF: 0.765 AC: 1615 AN: 2110

Alfa AF: 0.712 Hom.: 109457

Bravo AF: 0.751

Asia WGS AF: 0.888 AC: 3086 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		-0.91
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: rs506500; hg19: chr5-78414337;