Genetic Variant BHMT:c.33+1655T>C (chr5-79113573-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.99

Publications

7 publications found

Variant links:

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]

BHMT links:

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)

DMGDH links:

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ACMG classification

Classification was made for transcript

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 link	c.33+1655T>C		intron_variant	Intron 1 of 7	ENST00000274353.10	NP_001704.2	Q93088V9HWA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10 link	c.33+1655T>C		intron_variant	Intron 1 of 7	1	NM_001713.3	ENSP00000274353.5		Q93088

Frequencies

GnomAD3 genomes

AF:

0.630

AC:

95691

AN:

151942

Hom.:

30258

Cov.:

show subpopulations

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.:

AF XY:

0.631

AC XY:

46901

AN XY:

74314

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1844

3689

5533

7378

9222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.79

PhyloP100

-5.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over