19-41397794-T-G

Variant names:

Variant summary

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

The ENST00000540732.3(ENSG00000255730):c.211-12843T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,605,510 control chromosomes in the GnomAD database, including 15,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 907 hom., cov: 33)

Exomes 𝑓: 0.14 ( 14267 hom. )

Consequence

ENSG00000255730
ENST00000540732.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.433

Publications

25 publications found

Variant links:

Genes affected

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

BCKDHA Gene-Disease associations (from GenCC):

maple syrup urine disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
maple syrup urine disease type 1A
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health, ClinGen
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

BCKDHA 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=-0.97).

BP6

Variant 19-41397794-T-G is Benign according to our data. Variant chr19-41397794-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.-34T>G		upstream_gene_variant		ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.-34T>G		upstream_gene_variant			NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000255730	ENST00000540732.3 link	c.211-12843T>G		intron_variant	Intron 2 of 9	2		ENSP00000443246.1		F5H5P2
BCKDHA	ENST00000269980.7 link	c.-34T>G		upstream_gene_variant		1	NM_000709.4	ENSP00000269980.2		P12694-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15471

AN:

152214

Hom.:

908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0382

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0937

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.100

GnomAD2 exomes

AF:

0.115

AC:

28721

AN:

249866

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.0674

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.0528

Gnomad FIN exome

AF:

0.0966

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.136

AC:

197327

AN:

1453178

Hom.:

14267

Cov.:

AF XY:

0.137

AC XY:

99142

AN XY:

723392

show subpopulations

African (AFR)

AF:

0.0365

AC:

1215

AN:

33300

American (AMR)

AF:

0.0713

AC:

3184

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

3473

AN:

26076

East Asian (EAS)

AF:

0.0498

AC:

1976

AN:

39652

South Asian (SAS)

AF:

0.158

AC:

13583

AN:

86032

European-Finnish (FIN)

AF:

0.0973

AC:

5193

AN:

53390

Middle Eastern (MID)

AF:

0.163

AC:

902

AN:

5528

European-Non Finnish (NFE)

AF:

0.145

AC:

159816

AN:

1104462

Other (OTH)

AF:

0.133

AC:

7985

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

8969

17938

26908

35877

44846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5722

11444

17166

22888

28610

<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:

0.102

AC:

15470

AN:

152332

Hom.:

907

Cov.:

AF XY:

0.100

AC XY:

7455

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0382

AC:

1590

AN:

41588

American (AMR)

AF:

0.106

AC:

1621

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

493

AN:

3472

East Asian (EAS)

AF:

0.0463

AC:

240

AN:

5178

South Asian (SAS)

AF:

0.157

AC:

760

AN:

4832

European-Finnish (FIN)

AF:

0.0937

AC:

995

AN:

10622

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9380

AN:

68020

Other (OTH)

AF:

0.101

AC:

213

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

718

1436

2154

2872

3590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.121

Hom.:

1412

Bravo

AF:

0.0983

Asia WGS

AF:

0.100

AC:

346

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

BCKDHA-related disorder

Benign:1

Jul 21, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.93

(source)

DANN

Benign

0.50

PhyloP100

-0.43

PromoterAI

-0.13

Neutral

(source)

Mutation Taster

=300/0

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