chr5-79079399-C-T

Variant names:

• chr5-79079399-C-T
• rs60158007
• NM_017614.5:c.197C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017614.5(BHMT2):​c.197C>T​(p.Ala66Val) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,613,598 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (55 hom.)
• Consequence: BHMT2 NM_017614.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.80
• Publications: 6 publications found

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]

DMGDH Gene-Disease associations (from GenCC):

• dimethylglycine dehydrogenase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012861282).
• BP6: Variant 5-79079399-C-T is Benign according to our data. Variant chr5-79079399-C-T is described in ClinVar as Benign. ClinVar VariationId is 774305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2153/152152) while in subpopulation AFR AF = 0.048 (1990/41474). AF 95% confidence interval is 0.0462. There are 54 homozygotes in GnomAd4. There are 1004 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017614.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	NM_017614.5	MANE Select	c.197C>T	p.Ala66Val	missense	Exon 3 of 8	NP_060084.2
	BHMT2	NM_001178005.2		c.197C>T	p.Ala66Val	missense	Exon 3 of 7	NP_001171476.1	Q9H2M3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT2	ENST00000255192.8	TSL:1 MANE Select	c.197C>T	p.Ala66Val	missense	Exon 3 of 8	ENSP00000255192.3	Q9H2M3-1
	BHMT2	ENST00000896185.1		c.197C>T	p.Ala66Val	missense	Exon 3 of 8	ENSP00000566244.1
	BHMT2	ENST00000896179.1		c.197C>T	p.Ala66Val	missense	Exon 3 of 8	ENSP00000566238.1

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2143 AN: 152034 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00392 AC: 984 AN: 251190 AF XY: 0.00268

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00154 AC: 2253 AN: 1461446 Hom.: 55 Cov.: 30 AF XY: 0.00134 AC XY: 975 AN XY: 727036

African (AFR) AF: 0.0486 AC: 1625 AN: 33438

American (AMR) AF: 0.00387 AC: 173 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 174 AN: 1111748

Other (OTH) AF: 0.00348 AC: 210 AN: 60376

GnomAD4 genome AF: 0.0142 AC: 2153 AN: 152152 Hom.: 54 Cov.: 33 AF XY: 0.0135 AC XY: 1004 AN XY: 74372

African (AFR) AF: 0.0480 AC: 1990 AN: 41474

American (AMR) AF: 0.00726 AC: 111 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68020

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00518 Hom.: 29

Bravo AF: 0.0162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0463 AC: 204

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00460 AC: 558

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.8
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.023	D
Polyphen		0.92	P
Vest4		0.53
MVP		0.73
MPC		0.51
ClinPred		0.085	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.84
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -30

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

Other links and lift over

dbSNP: rs60158007; hg19: chr5-78375222;