5-79121335-G-A

Position:

• chr5-79121335-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001713.3(BHMT):​c.595G>A​(p.Gly199Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,614,174 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (63 hom.)
• Consequence: BHMT NM_001713.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.60

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01422286).
• BP6: Variant 5-79121335-G-A is Benign according to our data. Variant chr5-79121335-G-A is described in ClinVar as [Benign]. Clinvar id is 774306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BHMT	NM_001713.3	c.595G>A	p.Gly199Ser	missense_variant	5/8	ENST00000274353.10	NP_001704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BHMT	ENST00000274353.10	c.595G>A	p.Gly199Ser	missense_variant	5/8	1	NM_001713.3	ENSP00000274353	P1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 838 AN: 152214 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00476 AC: 1196 AN: 251424 Hom.: 13 AF XY: 0.00460 AC XY: 625 AN XY: 135894

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.00788

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00770 AC: 11258 AN: 1461842 Hom.: 63 Cov.: 33 AF XY: 0.00756 AC XY: 5497 AN XY: 727224

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00580

Gnomad4 NFE exome AF: 0.00923

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152332 Hom.: 4 Cov.: 31 AF XY: 0.00530 AC XY: 395 AN XY: 74494

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00575

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00709 Hom.: 17

Bravo AF: 0.00503

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00440 AC: 534

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00812

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.29
Sift	Benign	0.050	D
Sift4G	Uncertain	0.058	T
Polyphen		0.98	D
Vest4		0.81
MVP		0.48
MPC		0.16
ClinPred		0.064	T
GERP RS		5.3
Varity_R		0.71
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs59866108; hg19: chr5-78417158;