rs3213861

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.376-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,611,524 control chromosomes in the GnomAD database, including 304,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33842 hom., cov: 31)

Exomes 𝑓: 0.61 ( 270431 hom. )

Consequence

BCKDHA
NM_000709.4 intron

Scores

Splicing: ADA: 0.00009352

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.513

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=-0.71).

BP6

Variant 19-41414039-A-C is Benign according to our data. Variant chr19-41414039-A-C is described in ClinVar as [Benign]. Clinvar id is 93357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.376-10A>C		intron_variant	Intron 3 of 8	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.376-10A>C		intron_variant	Intron 3 of 8		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.376-10A>C		intron_variant	Intron 3 of 8	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.478-10A>C		intron_variant	Intron 4 of 9	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99731

AN:

151882

Hom.:

33799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.821

Gnomad AMI

AF:

0.769

Gnomad AMR

AF:

0.560

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.601

Gnomad OTH

AF:

0.638

GnomAD2 exomes

AF:

0.591

AC:

147875

AN:

250126

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.824

Gnomad AMR exome

AF:

0.478

Gnomad ASJ exome

AF:

0.626

Gnomad EAS exome

AF:

0.424

Gnomad FIN exome

AF:

0.656

Gnomad NFE exome

AF:

0.604

Gnomad OTH exome

AF:

0.607

GnomAD4 exome

AF:

0.606

AC:

884403

AN:

1459524

Hom.:

270431

Cov.:

AF XY:

0.605

AC XY:

439283

AN XY:

726178

show subpopulations

African (AFR)

AF:

0.832

AC:

27821

AN:

33450

American (AMR)

AF:

0.485

AC:

21671

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.624

AC:

16291

AN:

26128

East Asian (EAS)

AF:

0.456

AC:

18112

AN:

39692

South Asian (SAS)

AF:

0.584

AC:

50350

AN:

86218

European-Finnish (FIN)

AF:

0.655

AC:

34570

AN:

52808

Middle Eastern (MID)

AF:

0.637

AC:

3656

AN:

5742

European-Non Finnish (NFE)

AF:

0.608

AC:

674914

AN:

1110466

Other (OTH)

AF:

0.614

AC:

37018

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

18018

36036

54053

72071

90089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.657

AC:

99827

AN:

152000

Hom.:

33842

Cov.:

AF XY:

0.654

AC XY:

48581

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.821

AC:

34051

AN:

41486

American (AMR)

AF:

0.559

AC:

8551

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

2165

AN:

3462

East Asian (EAS)

AF:

0.430

AC:

2210

AN:

5138

South Asian (SAS)

AF:

0.588

AC:

2834

AN:

4820

European-Finnish (FIN)

AF:

0.661

AC:

6973

AN:

10556

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.601

AC:

40808

AN:

67936

Other (OTH)

AF:

0.638

AC:

1348

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1647

3293

4940

6586

8233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.623

Hom.:

14037

Bravo

AF:

0.656

Asia WGS

AF:

0.536

AC:

1864

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Benign:4

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.9

(source)

DANN

Benign

0.78

PhyloP100

-0.51

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

dbscSNV1_RF

Benign

0.066

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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rs3213861

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