5-79131036-G-C

Variant names:

• chr5-79131036-G-C
• rs148233515
• NM_001713.3:c.1141G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001713.3(BHMT):​c.1141G>C​(p.Glu381Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,808 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BHMT NM_001713.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.14

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]

ACMG classification

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=0.17087457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT	NM_001713.3	c.1141G>C	p.Glu381Gln	missense_variant	Exon 8 of 8	ENST00000274353.10	NP_001704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10	c.1141G>C	p.Glu381Gln	missense_variant	Exon 8 of 8	1	NM_001713.3	ENSP00000274353.5
BHMT	ENST00000524080.1	c.682G>C	p.Glu228Gln	missense_variant	Exon 5 of 5	2		ENSP00000428240.1
DMGDH	ENST00000518707.1	n.129-9684C>G		intron_variant	Intron 1 of 2	2
DMGDH	ENST00000520388.5	n.229-9684C>G		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251386 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135870

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461808 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727200

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.081
Sift	Benign	0.083	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.42	B;P
Vest4		0.18
MutPred		0.20		Gain of MoRF binding (P = 0.033);.;
MVP		0.41
MPC		0.13
ClinPred		0.56	D
GERP RS		4.7
Varity_R		0.26
gMVP		0.35

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

Other links and lift over

dbSNP: rs148233515; hg19: chr5-78426859;