rs284654

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000709.4(BCKDHA):c.995+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,609,446 control chromosomes in the GnomAD database, including 296,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30481 hom., cov: 31)

Exomes 𝑓: 0.60 ( 266512 hom. )

Consequence

BCKDHA
NM_000709.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.91

Publications

18 publications found

Variant links:

Genes affected

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:

ENSG00000255730 (HGNC:):

ENSG00000255730 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=-0.84).

BP6

Variant 19-41422819-G-A is Benign according to our data. Variant chr19-41422819-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.995+49G>A		intron_variant	Intron 7 of 8	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.992+49G>A		intron_variant	Intron 7 of 8		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.995+49G>A		intron_variant	Intron 7 of 8	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.1097+49G>A		intron_variant	Intron 8 of 9	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.628

AC:

95303

AN:

151664

Hom.:

30457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.724

Gnomad AMI

AF:

0.771

Gnomad AMR

AF:

0.549

Gnomad ASJ

AF:

0.623

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.659

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.600

Gnomad OTH

AF:

0.617

GnomAD2 exomes

AF:

0.583

AC:

144063

AN:

247068

AF XY:

0.584

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.471

Gnomad ASJ exome

AF:

0.625

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.657

Gnomad NFE exome

AF:

0.603

Gnomad OTH exome

AF:

0.603

GnomAD4 exome

AF:

0.603

AC:

878385

AN:

1457664

Hom.:

266512

Cov.:

AF XY:

0.602

AC XY:

436531

AN XY:

725144

show subpopulations

African (AFR)

AF:

0.731

AC:

24475

AN:

33462

American (AMR)

AF:

0.478

AC:

21351

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

16237

AN:

26104

East Asian (EAS)

AF:

0.459

AC:

18207

AN:

39660

South Asian (SAS)

AF:

0.582

AC:

50173

AN:

86214

European-Finnish (FIN)

AF:

0.656

AC:

33188

AN:

50628

Middle Eastern (MID)

AF:

0.630

AC:

3635

AN:

5766

European-Non Finnish (NFE)

AF:

0.607

AC:

674569

AN:

1110886

Other (OTH)

AF:

0.606

AC:

36550

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

19002

38004

57006

76008

95010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.628

AC:

95373

AN:

151782

Hom.:

30481

Cov.:

AF XY:

0.627

AC XY:

46467

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.724

AC:

29985

AN:

41408

American (AMR)

AF:

0.549

AC:

8369

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.623

AC:

2161

AN:

3468

East Asian (EAS)

AF:

0.433

AC:

2217

AN:

5126

South Asian (SAS)

AF:

0.585

AC:

2812

AN:

4808

European-Finnish (FIN)

AF:

0.659

AC:

6930

AN:

10512

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.600

AC:

40719

AN:

67902

Other (OTH)

AF:

0.616

AC:

1297

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1794

3588

5383

7177

8971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.594

Hom.:

14150

Bravo

AF:

0.624

Asia WGS

AF:

0.531

AC:

1845

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maple syrup urine disease

Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.073

(source)

DANN

Benign

0.53

PhyloP100

-1.9

PromoterAI

0.033

Neutral

(source)

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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rs284654

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