rs34442879

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000709.4(BCKDHA):c.452C>T(p.Thr151Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,613,696 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T151T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0079 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 84 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.31

Publications

13 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 -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000709.4

BP4

Computational evidence support a benign effect (MetaRNN=0.017781347).

BP6

Variant 19-41414125-C-T is Benign according to our data. Variant chr19-41414125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93361.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 = 0.00786 (1198/152328) while in subpopulation NFE AF = 0.0103 (701/68038). AF 95% confidence interval is 0.00967. There are 14 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.452C>T	p.Thr151Met	missense_variant	Exon 4 of 9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2 link	c.452C>T	p.Thr151Met	missense_variant	Exon 4 of 9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.452C>T	p.Thr151Met	missense_variant	Exon 4 of 9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3 link	c.554C>T	p.Thr185Met	missense_variant	Exon 5 of 10	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

1197

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00976

AC:

2447

AN:

250702

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00498

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.00895

AC:

13086

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

6488

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33480

American (AMR)

AF:

0.00436

AC:

195

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

140

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00541

AC:

467

AN:

86258

European-Finnish (FIN)

AF:

0.0251

AC:

1331

AN:

52932

Middle Eastern (MID)

AF:

0.0468

AC:

270

AN:

5768

European-Non Finnish (NFE)

AF:

0.00905

AC:

10061

AN:

1111984

Other (OTH)

AF:

0.00926

AC:

559

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

776

1552

2328

3104

3880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.00786

AC:

1198

AN:

152328

Hom.:

Cov.:

AF XY:

0.00869

AC XY:

647

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41572

American (AMR)

AF:

0.00510

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10610

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0103

AC:

701

AN:

68038

Other (OTH)

AF:

0.0123

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00943

Hom.:

Bravo

AF:

0.00627

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.0106

AC:

1290

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 18, 2016

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in Exome Aggregation Consortium. BCKDHA mutations are responsible for Maple syrup urine disease but it is not known if this variant has been ever seen in patients. -

Maple syrup urine disease

Benign:4

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Thr151Met variant, sometimes called p.Thr106Met due to a difference in cDNA numbering, in BCKDHA has been identified in a Turkish individual with maple syrup urine disease (PMID: 12118532), but has also been identified in >2% of European (Finnish) chromosomes and 9 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive maple syrup urine disease. -

Dec 18, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BCKDHA: BS2 -

Dec 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32193832, 31119508, 26990548, 14517957, 27535533, 27884173, 12118532, 21228398, 20981092, 22995991, 25087612) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Maple syrup urine disease type 1A

Benign:2

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2020

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

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;D;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

D;D;D;D

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.8

.;L;.;.

PhyloP100

1.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Uncertain

0.044

D;T;T;D

Polyphen

0.96

.;D;.;.

Vest4

0.18

MPC

1.2

ClinPred

0.023

GERP RS

4.7

Varity_R

0.15

gMVP

0.70

Mutation Taster

=57/43

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