1-100206304-ATT-AT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001918.5(DBT):c.1210-4delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,367,896 control chromosomes in the GnomAD database, including 29 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 30)

Exomes 𝑓: 0.028 ( 27 hom. )

Consequence

DBT
NM_001918.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.564

Publications

2 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 -16 ACMG points.

BP6

Variant 1-100206304-AT-A is Benign according to our data. Variant chr1-100206304-AT-A is described in ClinVar as Benign. ClinVar VariationId is 166981.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 = 0.0031 (461/148752) while in subpopulation AFR AF = 0.00849 (343/40380). AF 95% confidence interval is 0.00775. There are 2 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBT	NM_001918.5 link	c.1210-4delA		splice_region_variant, intron_variant	Intron 9 of 10	ENST00000370132.8	NP_001909.4	P11182

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DBT	ENST00000370132.8 link	c.1210-4delA	splice_region_variant, intron_variant	Intron 9 of 10	1	NM_001918.5	ENSP00000359151.3	P11182
DBT	ENST00000681617.1 link	c.1336-4delA	splice_region_variant, intron_variant	Intron 10 of 11			ENSP00000505544.1	A0A7P0Z494
DBT	ENST00000681780.1 link	c.667-4delA	splice_region_variant, intron_variant	Intron 10 of 11			ENSP00000505780.1	A0A7P0T9W1
ENSG00000285530	ENST00000835180.1 link	n.140-12339delT	intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

459

AN:

148654

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00263

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.000584

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.000640

Gnomad OTH

AF:

0.00146

GnomAD2 exomes

AF:

0.0311

AC:

6078

AN:

195454

AF XY:

0.0314

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.0547

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.0119

Gnomad FIN exome

AF:

0.0302

Gnomad NFE exome

AF:

0.0339

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0279

AC:

33971

AN:

1219144

Hom.:

Cov.:

AF XY:

0.0271

AC XY:

16463

AN XY:

607688

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0120

AC:

378

AN:

31516

American (AMR)

AF:

0.0422

AC:

1554

AN:

36822

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

495

AN:

22100

East Asian (EAS)

AF:

0.0149

AC:

515

AN:

34560

South Asian (SAS)

AF:

0.0211

AC:

1571

AN:

74442

European-Finnish (FIN)

AF:

0.0280

AC:

1230

AN:

43930

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5186

European-Non Finnish (NFE)

AF:

0.0291

AC:

26807

AN:

919790

Other (OTH)

AF:

0.0266

AC:

1353

AN:

50798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

4204

8408

12612

16816

21020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1044

2088

3132

4176

5220

<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:

0.00310

AC:

461

AN:

148752

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

244

AN XY:

72526

show subpopulations

African (AFR)

AF:

0.00849

AC:

343

AN:

40380

American (AMR)

AF:

0.00262

AC:

AN:

14870

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3428

East Asian (EAS)

AF:

0.000585

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

9836

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000640

AC:

AN:

67148

Other (OTH)

AF:

0.00145

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0241

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 12, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

PhyloP100

0.56

Mutation Taster

=95/5

polymorphism

(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