5-79079399-C-T

Position:

chr5-79079399-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.80

Variant links:

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]

BHMT2 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BHMT2	NM_017614.5 linkuse as main transcript	c.197C>T	p.Ala66Val	missense_variant	3/8	ENST00000255192.8	NP_060084.2
BHMT2	NM_001178005.2 linkuse as main transcript	c.197C>T	p.Ala66Val	missense_variant	3/7		NP_001171476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BHMT2	ENST00000255192.8 linkuse as main transcript	c.197C>T	p.Ala66Val	missense_variant	3/8	1	NM_017614.5	ENSP00000255192	P1	Q9H2M3-1

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2143

AN:

152034

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00392

AC:

984

AN:

251190

Hom.:

AF XY:

0.00268

AC XY:

364

AN XY:

135758

show subpopulations

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 SAS exome

AF:

0.000131

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.:

Cov.:

AF XY:

0.00134

AC XY:

975

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.0486

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.00348

GnomAD4 genome

AF:

0.0142

AC:

2153

AN:

152152

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

1004

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0480

Gnomad4 AMR

AF:

0.00726

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00251

Hom.:

Bravo

AF:

0.0162

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0463

AC:

204

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00460

AC:

558

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D;T

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.2

M;.;M

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.016

D;D;T

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.92

P;.;.

Vest4

0.53

MVP

0.73

MPC

0.51

ClinPred

0.085

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over