dbSNP rs115696850: DBT:c.1281+31T>G (chr1-100206199-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001918.5(DBT):c.1281+31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,508,738 control chromosomes in the GnomAD database, including 1,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 92 hom., cov: 30)

Exomes 𝑓: 0.041 ( 1374 hom. )

Consequence

DBT
NM_001918.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.52

Publications

7 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: ClinGen, Labcorp Genetics (formerly Invitae)
maple syrup urine disease type 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health
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 (BayesDel_noAF=-0.81).

BP6

Variant 1-100206199-A-C is Benign according to our data. Variant chr1-100206199-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0299 (4545/152060) while in subpopulation NFE AF = 0.0449 (3054/67992). AF 95% confidence interval is 0.0436. There are 92 homozygotes in GnomAd4. There are 2169 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 92 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001918.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DBT	NM_001918.5	MANE Select	c.1281+31T>G	intron	N/A	NP_001909.4	P11182
DBT	NM_001399969.1		c.738+31T>G	intron	N/A	NP_001386898.1	A0A7P0T9W1
DBT	NM_001399972.1		c.738+31T>G	intron	N/A	NP_001386901.1	A0A7P0T9W1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DBT	ENST00000370132.8	TSL:1 MANE Select	c.1281+31T>G	intron	N/A	ENSP00000359151.3	P11182
DBT	ENST00000681617.1		c.1407+31T>G	intron	N/A	ENSP00000505544.1	A0A7P0Z494
DBT	ENST00000875462.1		c.1281+31T>G	intron	N/A	ENSP00000545521.1

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4545

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00805

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0247

Gnomad ASJ

AF:

0.0484

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0449

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0317

AC:

7869

AN:

248570

AF XY:

0.0330

show subpopulations

Gnomad AFR exome

AF:

0.00697

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0423

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0432

Gnomad NFE exome

AF:

0.0465

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0407

AC:

55213

AN:

1356678

Hom.:

1374

Cov.:

AF XY:

0.0401

AC XY:

27293

AN XY:

680782

show subpopulations

African (AFR)

AF:

0.00725

AC:

227

AN:

31292

American (AMR)

AF:

0.0189

AC:

832

AN:

44130

Ashkenazi Jewish (ASJ)

AF:

0.0419

AC:

1069

AN:

25492

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39190

South Asian (SAS)

AF:

0.0104

AC:

866

AN:

83012

European-Finnish (FIN)

AF:

0.0433

AC:

2308

AN:

53304

Middle Eastern (MID)

AF:

0.0447

AC:

249

AN:

5566

European-Non Finnish (NFE)

AF:

0.0468

AC:

47637

AN:

1017858

Other (OTH)

AF:

0.0356

AC:

2024

AN:

56834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2538

5076

7613

10151

12689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1682

3364

5046

6728

8410

<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:

0.0299

AC:

4545

AN:

152060

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2169

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00803

AC:

333

AN:

41476

American (AMR)

AF:

0.0246

AC:

376

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

168

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0114

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0438

AC:

462

AN:

10552

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0449

AC:

3054

AN:

67992

Other (OTH)

AF:

0.0266

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

216

431

647

862

1078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0360

Hom.:

Bravo

AF:

0.0290

Asia WGS

AF:

0.00549

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.4

(source)

DANN

Benign

0.80

PhyloP100

2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over