5-79119314-C-T

Variant names:

• chr5-79119314-C-T
• rs35041410
• NM_001713.3:c.222C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001713.3(BHMT):​c.222C>T​(p.Phe74Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.00164 in 1,614,152 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (14 hom.)
• Consequence: BHMT NM_001713.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.88
• Publications: 3 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]

LOC124901012 (HGNC:):

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 5-79119314-C-T is Benign according to our data. Variant chr5-79119314-C-T is described in ClinVar as Benign. ClinVar VariationId is 711926.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 = 0.00834 (1270/152336) while in subpopulation AFR AF = 0.0285 (1183/41568). AF 95% confidence interval is 0.0271. There are 15 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001713.3. 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
	BHMT	NM_001713.3	MANE Select	c.222C>T	p.Phe74Phe	synonymous	Exon 3 of 8	NP_001704.2	Q93088

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHMT	ENST00000274353.10	TSL:1 MANE Select	c.222C>T	p.Phe74Phe	synonymous	Exon 3 of 8	ENSP00000274353.5	Q93088
	BHMT	ENST00000910530.1		c.222C>T	p.Phe74Phe	synonymous	Exon 3 of 8	ENSP00000580589.1
	BHMT	ENST00000910525.1		c.222C>T	p.Phe74Phe	synonymous	Exon 3 of 8	ENSP00000580584.1

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1264 AN: 152218 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00215 AC: 540 AN: 251386 AF XY: 0.00168

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000945 AC: 1382 AN: 1461816 Hom.: 14 Cov.: 30 AF XY: 0.000836 AC XY: 608 AN XY: 727204

African (AFR) AF: 0.0292 AC: 978 AN: 33468

American (AMR) AF: 0.00208 AC: 93 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000109 AC: 121 AN: 1111998

Other (OTH) AF: 0.00222 AC: 134 AN: 60392

GnomAD4 genome AF: 0.00834 AC: 1270 AN: 152336 Hom.: 15 Cov.: 33 AF XY: 0.00834 AC XY: 621 AN XY: 74476

African (AFR) AF: 0.0285 AC: 1183 AN: 41568

American (AMR) AF: 0.00366 AC: 56 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68040

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00331 Hom.: 4

Bravo AF: 0.0103

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

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
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		3.9
Mutation Taster		=89/11	polymorphism

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: rs35041410; hg19: chr5-78415137;