5-79069802-C-T

Variant summary

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

The NM_017614.5(BHMT2):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000778 in 1,284,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

BHMT2
NM_017614.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.241
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12419948).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BHMT2NM_017614.5 linkc.20C>T p.Pro7Leu missense_variant Exon 1 of 8 ENST00000255192.8 NP_060084.2 Q9H2M3-1A0A024RAQ0
DMGDHNM_013391.3 linkc.-182G>A upstream_gene_variant ENST00000255189.8 NP_037523.2 Q9UI17-1B3KQ84

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BHMT2ENST00000255192.8 linkc.20C>T p.Pro7Leu missense_variant Exon 1 of 8 1 NM_017614.5 ENSP00000255192.3 Q9H2M3-1
DMGDHENST00000255189.8 linkc.-182G>A upstream_gene_variant 1 NM_013391.3 ENSP00000255189.3 Q9UI17-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000231
AC:
2
AN:
86678
Hom.:
0
AF XY:
0.0000420
AC XY:
2
AN XY:
47580
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000142
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
7.78e-7
AC:
1
AN:
1284714
Hom.:
0
Cov.:
32
AF XY:
0.00000158
AC XY:
1
AN XY:
631896
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:
0.0000158
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000954
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 12, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.20C>T (p.P7L) alteration is located in exon 1 (coding exon 1) of the BHMT2 gene. This alteration results from a C to T substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by a leucine (L). 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
0.093
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.0078
T;.
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.70
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L;L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.026
Sift
Uncertain
0.026
D;T
Sift4G
Uncertain
0.036
D;D
Polyphen
0.31
B;.
Vest4
0.27
MVP
0.44
MPC
0.19
ClinPred
0.13
T
GERP RS
1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.039
gMVP
0.47

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: rs750536578; hg19: chr5-78365625; API