chr5-79083001-C-T

Variant names:

• chr5-79083001-C-T
• rs41272270
• NM_017614.5:c.598+45C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017614.5(BHMT2):​c.598+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.091 in 1,608,400 control chromosomes in the GnomAD database, including 7,323 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.070 (507 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6816 hom.)
• Consequence: BHMT2 NM_017614.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 9 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHMT2	NM_017614.5	c.598+45C>T		intron_variant	Intron 5 of 7	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2	c.406+45C>T		intron_variant	Intron 4 of 6		NP_001171476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHMT2	ENST00000255192.8	c.598+45C>T		intron_variant	Intron 5 of 7	1	NM_017614.5	ENSP00000255192.3

Frequencies

GnomAD3 genomes AF: 0.0697 AC: 10586 AN: 151856 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.0632

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0941

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0655

GnomAD2 exomes AF: 0.0725 AC: 18050 AN: 248924 AF XY: 0.0740

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.0626

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0892

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0809

GnomAD4 exome AF: 0.0933 AC: 135854 AN: 1456426 Hom.: 6816 Cov.: 30 AF XY: 0.0924 AC XY: 66926 AN XY: 724080

African (AFR) AF: 0.0174 AC: 581 AN: 33306

American (AMR) AF: 0.0430 AC: 1912 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 1699 AN: 26054

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39648

South Asian (SAS) AF: 0.0536 AC: 4590 AN: 85706

European-Finnish (FIN) AF: 0.0900 AC: 4806 AN: 53380

Middle Eastern (MID) AF: 0.0911 AC: 523 AN: 5742

European-Non Finnish (NFE) AF: 0.106 AC: 117020 AN: 1107974

Other (OTH) AF: 0.0783 AC: 4711 AN: 60176

GnomAD4 genome AF: 0.0697 AC: 10586 AN: 151974 Hom.: 507 Cov.: 32 AF XY: 0.0690 AC XY: 5127 AN XY: 74268

African (AFR) AF: 0.0222 AC: 919 AN: 41446

American (AMR) AF: 0.0532 AC: 812 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0632 AC: 219 AN: 3464

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0627 AC: 302 AN: 4818

European-Finnish (FIN) AF: 0.0941 AC: 989 AN: 10506

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7104 AN: 67986

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

Alfa AF: 0.0922 Hom.: 424

Bravo AF: 0.0632

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.68
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41272270; hg19: chr5-78378824; COSMIC: COSV107297249; COSMIC: COSV107297249;