1-100206504-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001918.5(DBT):c.1150A>G(p.Ser384Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 1,613,388 control chromosomes in the GnomAD database, including 665,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S384S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 58729 hom., cov: 31)

Exomes 𝑓: 0.91 ( 607129 hom. )

Consequence

DBT
NM_001918.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.94

Publications

53 publications found

Variant links:

Genes affected

DBT (HGNC:2698): (dihydrolipoamide branched chain transacylase E2) The branched-chain alpha-keto acid dehydrogenase complex (BCKD) is an inner-mitochondrial enzyme complex involved in the breakdown of the branched-chain amino acids isoleucine, leucine, and valine. The BCKD complex is thought to be composed of a core of 24 transacylase (E2) subunits, and associated decarboxylase (E1), dehydrogenase (E3), and regulatory subunits. This gene encodes the transacylase (E2) subunit. Mutations in this gene result in maple syrup urine disease, type 2. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

DBT Gene-Disease associations (from GenCC):

maple syrup urine disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
maple syrup urine disease type 2
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
classic maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermediate maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermittent maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thiamine-responsive maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DBT links:

ENSG00000285530 (HGNC:):

ENSG00000285530 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.0305434E-6).

BP6

Variant 1-100206504-T-C is Benign according to our data. Variant chr1-100206504-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBT	NM_001918.5 link	c.1150A>G	p.Ser384Gly	missense_variant	Exon 9 of 11	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DBT	ENST00000370132.8 link	c.1150A>G	p.Ser384Gly	missense_variant	Exon 9 of 11	1	NM_001918.5	ENSP00000359151.3
DBT	ENST00000681617.1 link	c.1276A>G	p.Ser426Gly	missense_variant	Exon 10 of 12			ENSP00000505544.1
DBT	ENST00000681780.1 link	c.607A>G	p.Ser203Gly	missense_variant	Exon 10 of 12			ENSP00000505780.1
ENSG00000285530	ENST00000835180.1 link	n.140-12140T>C		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.876

AC:

133222

AN:

152050

Hom.:

58703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.852

Gnomad AMR

AF:

0.917

Gnomad ASJ

AF:

0.913

Gnomad EAS

AF:

0.967

Gnomad SAS

AF:

0.953

Gnomad FIN

AF:

0.934

Gnomad MID

AF:

0.908

Gnomad NFE

AF:

0.911

Gnomad OTH

AF:

0.890

GnomAD2 exomes

AF:

0.917

AC:

230704

AN:

251468

AF XY:

0.920

show subpopulations

Gnomad AFR exome

AF:

0.763

Gnomad AMR exome

AF:

0.955

Gnomad ASJ exome

AF:

0.917

Gnomad EAS exome

AF:

0.969

Gnomad FIN exome

AF:

0.931

Gnomad NFE exome

AF:

0.908

Gnomad OTH exome

AF:

0.913

GnomAD4 exome

AF:

0.911

AC:

1331229

AN:

1461220

Hom.:

607129

Cov.:

AF XY:

0.913

AC XY:

663563

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.763

AC:

25540

AN:

33454

American (AMR)

AF:

0.951

AC:

42554

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.915

AC:

23924

AN:

26134

East Asian (EAS)

AF:

0.980

AC:

38906

AN:

39692

South Asian (SAS)

AF:

0.952

AC:

82111

AN:

86250

European-Finnish (FIN)

AF:

0.929

AC:

49602

AN:

53390

Middle Eastern (MID)

AF:

0.892

AC:

5142

AN:

5764

European-Non Finnish (NFE)

AF:

0.907

AC:

1008536

AN:

1111428

Other (OTH)

AF:

0.909

AC:

54914

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6086

12172

18257

24343

30429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21456

42912

64368

85824

107280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.876

AC:

133297

AN:

152168

Hom.:

58729

Cov.:

AF XY:

0.880

AC XY:

65449

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.765

AC:

31723

AN:

41474

American (AMR)

AF:

0.917

AC:

14026

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.913

AC:

3166

AN:

3468

East Asian (EAS)

AF:

0.967

AC:

5001

AN:

5174

South Asian (SAS)

AF:

0.952

AC:

4585

AN:

4814

European-Finnish (FIN)

AF:

0.934

AC:

9897

AN:

10600

Middle Eastern (MID)

AF:

0.912

AC:

268

AN:

294

European-Non Finnish (NFE)

AF:

0.911

AC:

61969

AN:

68022

Other (OTH)

AF:

0.891

AC:

1885

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

808

1615

2423

3230

4038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.902

Hom.:

160482

Bravo

AF:

0.869

TwinsUK

AF:

0.906

AC:

3361

ALSPAC

AF:

0.907

AC:

3495

ESP6500AA

AF:

0.775

AC:

3414

ESP6500EA

AF:

0.902

AC:

7761

ExAC

AF:

0.914

AC:

110942

Asia WGS

AF:

0.926

AC:

3223

AN:

3478

EpiCase

AF:

0.905

EpiControl

AF:

0.904

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Aug 24, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Maple syrup urine disease

Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29306928, 14517957, 26232051, 27884173, 9621512, 20981092) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maple syrup urine disease type 1A

Benign:1

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.15

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.017

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-1.0

PhyloP100

1.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

3.0

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.042

MPC

0.29

ClinPred

0.00015

GERP RS

4.4

gMVP

0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over