5-79080760-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_017614.5(BHMT2):c.332G>T(p.Gly111Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000984 in 1,605,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

BHMT2
NM_017614.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Publications

0 publications found

Variant links:

Genes affected

BHMT2 (HGNC:1048): (betaine--homocysteine S-methyltransferase 2) Homocysteine is a sulfur-containing amino acid that plays a crucial role in methylation reactions. Transfer of the methyl group from betaine to homocysteine creates methionine, which donates the methyl group to methylate DNA, proteins, lipids, and other intracellular metabolites. The protein encoded by this gene is one of two methyl transferases that can catalyze the transfer of the methyl group from betaine to homocysteine. Anomalies in homocysteine metabolism have been implicated in disorders ranging from vascular disease to neural tube birth defects such as spina bifida. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

BHMT2 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

DMGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017614.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	NM_017614.5	MANE Select	c.332G>T	p.Gly111Val	missense	Exon 4 of 8	NP_060084.2
	BHMT2	NM_001178005.2		c.258+1300G>T		intron	N/A	NP_001171476.1	Q9H2M3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.332G>T	p.Gly111Val	missense	Exon 4 of 8	ENSP00000255192.3	Q9H2M3-1
BHMT2	ENST00000896185.1		c.332G>T	p.Gly111Val	missense	Exon 4 of 8	ENSP00000566244.1
BHMT2	ENST00000896179.1		c.332G>T	p.Gly111Val	missense	Exon 4 of 8	ENSP00000566238.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000162

AC:

AN:

240314

AF XY:

0.000254

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.0000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.000349

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1452874

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

722594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32826

American (AMR)

AF:

0.0000702

AC:

AN:

42706

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

38958

South Asian (SAS)

AF:

0.000618

AC:

AN:

84098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000712

AC:

AN:

1109132

Other (OTH)

AF:

0.000166

AC:

AN:

60066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000203

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000173

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.9

PhyloP100

7.6

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.65

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MutPred

0.96

Gain of sheet (P = 0.0477)

MVP

0.90

MPC

0.81

ClinPred

0.50

GERP RS

6.2

Varity_R

0.89

gMVP

0.91

Mutation Taster

=22/78

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over