rs11549936

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.116C>A(p.Pro39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,072 control chromosomes in the GnomAD database, including 13,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.089 ( 764 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12540 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.80

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 (MetaRNN=0.0015936196).

BP6

Variant 19-41410644-C-A is Benign according to our data. Variant chr19-41410644-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 93341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.116C>A	p.Pro39His	missense_variant	Exon 2 of 9	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.116C>A	p.Pro39His	missense_variant	Exon 2 of 9		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.116C>A	p.Pro39His	missense_variant	Exon 2 of 9	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.218C>A	p.Pro73His	missense_variant	Exon 3 of 10	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.0890

AC:

13543

AN:

152128

Hom.:

765

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0715

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.0927

GnomAD2 exomes

AF:

0.0988

AC:

24826

AN:

251376

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.0629

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0741

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.125

AC:

183247

AN:

1461826

Hom.:

12540

Cov.:

AF XY:

0.126

AC XY:

91343

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0200

AC:

669

AN:

33480

American (AMR)

AF:

0.0664

AC:

2969

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3357

AN:

26134

East Asian (EAS)

AF:

0.000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.116

AC:

9997

AN:

86256

European-Finnish (FIN)

AF:

0.0739

AC:

3949

AN:

53408

Middle Eastern (MID)

AF:

0.128

AC:

740

AN:

5764

European-Non Finnish (NFE)

AF:

0.139

AC:

154498

AN:

1111982

Other (OTH)

AF:

0.117

AC:

7048

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9859

19718

29578

39437

49296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0889

AC:

13541

AN:

152246

Hom.:

764

Cov.:

AF XY:

0.0861

AC XY:

6409

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0228

AC:

946

AN:

41550

American (AMR)

AF:

0.100

AC:

1529

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

474

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.104

AC:

502

AN:

4828

European-Finnish (FIN)

AF:

0.0715

AC:

759

AN:

10616

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.132

AC:

8964

AN:

67996

Other (OTH)

AF:

0.0913

AC:

193

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

639

1277

1916

2554

3193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.115

Hom.:

2612

Bravo

AF:

0.0874

TwinsUK

AF:

0.142

AC:

528

ALSPAC

AF:

0.148

AC:

571

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.136

AC:

1170

ExAC

AF:

0.0983

AC:

11938

Asia WGS

AF:

0.0430

AC:

150

AN:

3478

EpiCase

AF:

0.146

EpiControl

AF:

0.140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 17, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maple syrup urine disease

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 08, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BCKDHA c.116C>A (p.Pro39His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11936/121154 control chromosomes (711 homozygotes) at a frequency of 0.0985192, which is approximately 59 times the estimated maximal expected allele frequency of a pathogenic BCKDHA variant (0.0016771), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple affected individuals who also carried other variants in BCKDHB that can explain the phenotype, and authors interpreted the variant of interest as silent variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Maple syrup urine disease type 1A

Benign:1

Sep 16, 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

0.062

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Benign

0.047

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.026

.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.13

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-0.55

.;N;.

PhyloP100

-1.8

PrimateAI

Benign

0.33

PROVEAN

Benign

0.16

N;N;N

REVEL

Uncertain

0.35

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.047

MPC

0.20

ClinPred

0.0013

GERP RS

-4.9

PromoterAI

0.0078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.034

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs11549936

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