5-79080775-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017614.5(BHMT2):​c.347C>A​(p.Thr116Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,050 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 0.0000066 ( 0 hom., cov: 32)

Consequence

BHMT2
NM_017614.5 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BHMT2NM_017614.5 linkc.347C>A p.Thr116Lys missense_variant Exon 4 of 8 ENST00000255192.8 NP_060084.2 Q9H2M3-1A0A024RAQ0
BHMT2NM_001178005.2 linkc.258+1315C>A intron_variant Intron 3 of 6 NP_001171476.1 Q9H2M3-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BHMT2ENST00000255192.8 linkc.347C>A p.Thr116Lys missense_variant Exon 4 of 8 1 NM_017614.5 ENSP00000255192.3 Q9H2M3-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152050
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152050
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.347C>A (p.T116K) alteration is located in exon 4 (coding exon 4) of the BHMT2 gene. This alteration results from a C to A substitution at nucleotide position 347, causing the threonine (T) at amino acid position 116 to be replaced by a lysine (K). 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
0.61
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.035
T;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.068
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-0.84
T
MutationAssessor
Pathogenic
3.7
H;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-4.3
D;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0030
D;D
Sift4G
Benign
0.098
T;D
Polyphen
0.95
P;.
Vest4
0.80
MutPred
0.71
Gain of methylation at T116 (P = 0.003);.;
MVP
0.74
MPC
0.54
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.63
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1419233285; hg19: chr5-78376598; API