BHMT p.Ile187Thr

Variant names:

• chr5-79121300-T-C
• rs542592055
• NM_001713.3:c.560T>C
• BHMT p.Ile187Thr

Your query was ambiguous. Multiple possible variants found:

• chr5-79121300-T-C
• chr5-79121300-TT-CA
• chr5-79121300-TT-CC
• chr5-79121300-TT-CG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_001713.3(BHMT):c.560T>C (p.Ile187Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,220 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.64). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I187S: Uncertain_significance (ClinVar VariationId 3824273, 1 star) The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BHMT NM_001713.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64
• Publications: 1 publications found

Genes affected

BHMT (HGNC:1047): (betaine--homocysteine S-methyltransferase) This gene encodes a cytosolic enzyme that catalyzes the conversion of betaine and homocysteine to dimethylglycine and methionine, respectively. Defects in this gene could lead to hyperhomocyst(e)inemia, but such a defect has not yet been observed. [provided by RefSeq, Jul 2008]

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: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000015, AC = 1 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001713.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BHMT NM_001713.3	MANE Select	c.560T>C p.Ile187Thr	missense	Exon 5 of 8	Prot: NP_001704.2 UniProt:

BHMT NM_001713.3

MANE Select

HGVSc / HGVSpc.560T>Cp.Ile187Thr

Exon rankExon 5 of 8

missense

Prot: NP_001704.2UniProt: Q93088

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BHMT ENST00000274353.10	TSL:1MANE Select	c.560T>C p.Ile187Thr	missense	Exon 5 of 8	Prot: ENSP00000274353.5 UniProt:
	BHMT ENST00000910530.1		c.560T>C p.Ile187Thr	missense	Exon 5 of 8	Prot: ENSP00000580589.1 UniProt:
	BHMT ENST00000910525.1		c.560T>C p.Ile187Thr	missense	Exon 5 of 8	Prot: ENSP00000580584.1 UniProt:

BHMT ENST00000274353.10

TSL:1MANE Select

HGVSc / HGVSpc.560T>Cp.Ile187Thr

Exon rankExon 5 of 8

missense

Prot: ENSP00000274353.5UniProt: Q93088

BHMT ENST00000910530.1

HGVSc / HGVSpc.560T>Cp.Ile187Thr

Exon rankExon 5 of 8

missense

Prot: ENSP00000580589.1UniProt: A0ACI8SI12

BHMT ENST00000910525.1

HGVSc / HGVSpc.560T>Cp.Ile187Thr

Exon rankExon 5 of 8

missense

Prot: ENSP00000580584.1UniProt: A0ACI8SHS3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152220	Cov:31
GnomAD4 exome Warning	AF: 6.84e-7	AC:1	Hom:0	AN:1461872	Cov:33
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152220	Cov:31
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000234	AC:1	Hom:0	AN:42692	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122774	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000129	1	77672	0.00	0	139318

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.64
GPN-Star LLR	N/A	-7.5
GPN-Star score	N/A	7.5
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Uncertain	2.4	M
PhyloP100	Pathogenic	7.6
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.2e-153
REVEL	Uncertain	0.58
Sift	Benign	0.058	T
Sift4G	Benign	0.083	T
Varity_R	N/A	0.66
VESM-3B	Benign	-10

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs542592055;

hg19: chr5-78417123;

COSMIC: COSV104568972;

COSMIC: COSV104568972;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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