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GeneBe

5-79077595-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017614.5(BHMT2):c.149T>C(p.Ile50Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BHMT2
NM_017614.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13358387).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BHMT2NM_017614.5 linkuse as main transcriptc.149T>C p.Ile50Thr missense_variant 2/8 ENST00000255192.8
BHMT2NM_001178005.2 linkuse as main transcriptc.149T>C p.Ile50Thr missense_variant 2/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BHMT2ENST00000255192.8 linkuse as main transcriptc.149T>C p.Ile50Thr missense_variant 2/81 NM_017614.5 P1Q9H2M3-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461716
Hom.:
0
Cov.:
39
AF XY:
0.00
AC XY:
0
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31

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 GeneticsFeb 05, 2024The c.149T>C (p.I50T) alteration is located in exon 2 (coding exon 2) of the BHMT2 gene. This alteration results from a T to C substitution at nucleotide position 149, causing the isoleucine (I) at amino acid position 50 to be replaced by a threonine (T). 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
Benign
0.068
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
Cadd
Benign
18
Dann
Benign
0.84
DEOGEN2
Benign
0.024
T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.79
T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Benign
0.039
Sift
Uncertain
0.0030
D;T
Sift4G
Uncertain
0.037
D;D
Polyphen
0.15
B;.
Vest4
0.14
MutPred
0.65
Gain of disorder (P = 0.0132);Gain of disorder (P = 0.0132);
MVP
0.22
MPC
0.23
ClinPred
0.42
T
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.28
gMVP
0.54

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: rs1755696767; hg19: chr5-78373418; API