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GeneBe

5-79080760-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

9
5
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BHMT2NM_017614.5 linkuse as main transcriptc.332G>T p.Gly111Val missense_variant 4/8 ENST00000255192.8
BHMT2NM_001178005.2 linkuse as main transcriptc.258+1300G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BHMT2ENST00000255192.8 linkuse as main transcriptc.332G>T p.Gly111Val missense_variant 4/81 NM_017614.5 P1Q9H2M3-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152106
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000162
AC:
39
AN:
240314
Hom.:
0
AF XY:
0.000254
AC XY:
33
AN XY:
130046
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 SAS exome
AF:
0.000603
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.:
0
Cov.:
30
AF XY:
0.000127
AC XY:
92
AN XY:
722594
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000702
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000618
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000712
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000941
AC XY:
7
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000203
Hom.:
0
Bravo
AF:
0.000140
ExAC
AF:
0.000173
AC:
21

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.332G>T (p.G111V) alteration is located in exon 4 (coding exon 4) of the BHMT2 gene. This alteration results from a G to T substitution at nucleotide position 332, causing the glycine (G) at amino acid position 111 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.28
Cadd
Uncertain
24
Dann
Uncertain
1.0
DEOGEN2
Benign
0.24
T;T
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.036
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Pathogenic
3.9
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-7.3
D;D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.016
D;T
Sift4G
Uncertain
0.0020
D;T
Polyphen
1.0
D;.
Vest4
0.89
MutPred
0.96
Gain of sheet (P = 0.0477);.;
MVP
0.90
MPC
0.81
ClinPred
0.50
T
GERP RS
6.2
Varity_R
0.89
gMVP
0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770007608; hg19: chr5-78376583; API