chr5-79121272-G-T

Variant names:

• chr5-79121272-G-T
• rs548757864
• NM_001713.3:c.532G>T
• BHMT p.Gly178Cys

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 (ACMG Germline Pathogenicity v2019). PM2

The NM_001713.3(BHMT):c.532G>T (p.Gly178Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000155 (AC=25) in the gnomAD database across 1,614,066 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000118. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BHMT NM_001713.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000118 — very rare for unknown gene (threshold 0.001) — PM2 moderate.

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.532G>T p.Gly178Cys	missense	Exon 5 of 8	Prot: NP_001704.2 UniProt:

BHMT NM_001713.3

MANE Select

HGVSc / HGVSpc.532G>Tp.Gly178Cys

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.532G>T p.Gly178Cys	missense	Exon 5 of 8	Prot: ENSP00000274353.5 UniProt:
	BHMT ENST00000910530.1		c.532G>T p.Gly178Cys	missense	Exon 5 of 8	Prot: ENSP00000580589.1 UniProt:
	BHMT ENST00000910525.1		c.532G>T p.Gly178Cys	missense	Exon 5 of 8	Prot: ENSP00000580584.1 UniProt:

BHMT ENST00000274353.10

TSL:1MANE Select

HGVSc / HGVSpc.532G>Tp.Gly178Cys

Exon rankExon 5 of 8

missense

Prot: ENSP00000274353.5UniProt: Q93088

BHMT ENST00000910530.1

HGVSc / HGVSpc.532G>Tp.Gly178Cys

Exon rankExon 5 of 8

missense

Prot: ENSP00000580589.1UniProt: A0ACI8SI12

BHMT ENST00000910525.1

HGVSc / HGVSpc.532G>Tp.Gly178Cys

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152204	Cov:31
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251494	Cov:
GnomAD4 exome	AF: 0.0000150	AC:22	Hom:0	AN:1461862	Cov:33
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152204	Cov:31
TOPMed (Bravo)	AF: 0.0000113	AC:3	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5176	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000299	2	66884
SCHEMA(Schizophrenia)	0.00	0	67870	0.0000150	2	133324

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.66
GPN-Star LLR	N/A	-7.9
GPN-Star score	N/A	7.9
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.39	T
Mutation Taster	N/A	8/92	disease causing
MutationAssessor	Pathogenic	3.2	M
PhyloP100	Pathogenic	9.6
popEVE	Benign	-3.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Varity_R	N/A	0.96
VESM-3B	Benign	-10

Showing 28 of 28 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: rs548757864;

hg19: chr5-78417095;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar